Benzimidazoles as corticotropin release factor antagonists

ABSTRACT

The present invention describes novel benzimidazoles of formula: or pharmaceutically acceptable salt forms thereof, which are useful as CRF antagonists.

This application is a continuation of provisional patent application Ser. No. 60/091,575 filed on Jul. 2, 1998.

FIELD OF THE INVENTION

This invention relates to novel benzimidazoles, pharmaceutical compositions containing the same and methods of using same in the treatment of psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing corticotropin releasing factor (CRF), including but not limited to disorders induced or facilitated by CRF.

BACKGROUND

Corticotropin releasing factor, a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohisto-chemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provides evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist α-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn, Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (α-helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

In view of the above, efficacious and specific antagonists of CRF are desired as potentially valuable therapeutic agents for the treatment of psychiatric disorders and neurological diseases. It is thus desirable to discover new CRF antagonists.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel benzimidazoles which are useful as CRF antagonists or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

It is another object of the present invention to provide a method for treating psychiatric disorders and neurological diseases comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors, discovery that compounds of formula I: ##STR2## or pharmaceutically acceptable salt forms thereof, wherein R¹, R², R³, R⁷, R⁸, X and D are defined below, are CRF antagonists.

DETAILED DESCRIPTION OF THE INVENTION

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR3## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

D is an aryl or heteroaryl group attached through an unsaturated carbon atom;

X is selected from the group CH--R⁹, N--R¹⁰, O, S(O)_(n) and a bond;

n is 0, 1 or 2;

R¹ is selected from the group C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, --SO₂ --C₁₋₁₀ alkyl, --SO₂ --R^(1a) and --SO₂ --R^(1b) ;

R¹ is substituted with 0-1 substituents selected from the group --CN, --S(O)_(n) R^(14b), --COR^(13a), --CO₂ R^(13a), --NR^(15a) COR^(13a), --N(COR^(13a))₂, --NR^(15a) CONR^(13a) R^(16a), --NR^(15a) CO₂ R^(14b), --CONR^(13a) R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group --O--, --S(O)_(n) --, --NR^(13a) --, --NCO₂ R^(14b) --, --NCOR^(14b) -- and --NSO₂ R^(14b) --, and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R^(13a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ;

R¹ is also substituted with 0-3 substituents independently selected at each occurrence from the group R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --OR^(13a), --NR^(13a) R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by --O--;

provided that R¹ is other than a cyclohexyl--(CH₂)₂ -- group;

R^(1a) is aryl and is selected from the group phenyl, naphthyl, indanyl and indenyl, each R1a being substituted with 0-1 --OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, SH, --S(O)_(n) R¹⁸, --COR¹⁷, --OC(O)R¹⁸, --NR^(15a) COR¹⁷, --N(COR¹⁷)₂, --NR^(15a) CONR^(17a) R^(19a), --NR^(15a) CO₂ R⁸, --NR^(17a) R^(19a), and --CONR^(17a) R^(19a) ;

R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR¹⁷, SH, --S(O)_(m) R¹⁸, --COR¹⁷, --OC(O)R¹⁸, --NR^(15a) COR¹⁷, --N(COR¹⁷)₂, --NR^(15a) CONR^(17a) R^(19a), --NR^(15a) CO₂ R¹⁸, --NR^(17a) R^(19a), and --CONR^(17a) R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ;

R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR^(13a), SH, --S(O)_(n) R^(14b), --COR^(13a), --OC(O)R^(14b), --NR^(15a) COR^(13a), --N(COR^(13a))₂, --NR^(15a) CONR^(13a) R^(16a), --NR^(15a) CO₂ R^(14b), --NR^(13a) R^(16a), and --CONR^(13a) R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(13a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) and wherein any sulfur atom is optionally monooxidized or dioxidized;

provided that R¹ is other than a --(CH₂)₁₋₄ -aryl, --(CH₂)₁₋₄ -heteroaryl, or --(CH₂)₁₋₄ -heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted;

R² is selected from the group C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group --CN, hydroxy, halo and C₁₋₄ alkoxy;

alternatively R², in the case where x is a bond, is selected from the group --CN, CF₃ and C₂ F₅ ;

R³, R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, I, --CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)_(2a) amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino; provided that when R¹ is unsubstituted C₁₋₁₀ alkyl, then R³ is other than substituted or unsubstituted phenyl;

R⁹ and R¹⁰ are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

R¹³ is selected from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)--, heteroaryl and heteroaryl (C₁₋₄ alkyl)--;

R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)--, heteroaryl and heteroaryl(C₁₋₄ alkyl)-- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

R¹⁷ is selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴ S(O)_(n) --C₁₋₄ alkyl, and R^(17b) R^(19b) N--C₂₋₄ alkyl;

R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

alternatively, in an NR¹⁷ R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂ R¹⁴, COR¹⁴ and SO₂ R¹⁴ ;

alternatively, in an NR^(17b) R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂ R¹⁴, COR¹⁴ and SO₂ R¹⁴ ;

R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

aryl is independently selected at each occurrence from the group phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, --OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, --NO₂, SH, --S(O)_(n) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CONR¹⁷ R¹⁹, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF₃, C₂ F₅, OCF₃, SO₂ Me and acetyl;

heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR¹⁷, SH, --S(O)_(m) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CONR¹⁷ R¹⁹, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R¹⁵, CO₂ R^(14a), COR^(14a) and SO₂ R^(14a) ; and,

provided that when D is imidazole or triazole, R¹ is other than unsubstituted C₁₋₆ linear or branched alkyl or C₃₋₆ cycloalkyl.

[2a] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

X is selected from the group O, S(O)_(n) and a bond;

n is 0, 1 or 2;

R¹ is selected from the group C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₆ alkyl;

R¹ is substituted with 0-1 substituents selected from the group --CN, --S(O)_(n) R^(14b), --COR^(13a), --CO₂ R^(13a), and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group --O--, --S(O)_(n) --, --NR^(13a) --, --NCO₂ R^(14b) --, --NCOR^(14b) -- and --NSO₂ R^(14b) --;

R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, CF₂ CF₃, --OR^(13a), --NR^(13a) R^(16a), C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by --O--;

provided that R¹ is other than a cyclohexyl--(CH₂)₂ -- group;

R^(1a) is aryl and is selected from the group phenyl and indanyl, each R^(1a) being substituted with 0-1 --OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, --CN, --S(O)_(n) R¹⁸, --COR¹⁷, --NR^(17a) R^(19a), and CONR^(17a) R^(19a) ;

R^(1b) is heteroaryl and is selected from the group pyridyl, pyrimidinyl, furanyl, thienyl, imidazolyl, thiazolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, CF₃, --CN, --OR¹⁷, --S(O)_(m) R¹⁸, --COR¹⁷, --NR^(17a) R^(19a), and --CONR^(17a) R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(15a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ;

provided that R¹ is other than a --(CH₂)₁₋₄ -aryl or --(CH₂)₁₋₄ -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R² is selected from the group C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl and is substituted with 0-1 substituents selected from the group --CN, OH, Cl, F, and C₁₋₄ alkoxy;

R³, R⁷ and R⁸ are independently selected at each occurrence from the group H, Br, Cl, F, --CN, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, NH₂, C₁₋₄ alkylamino, and (C₁₋₄ alkyl)₂ -amino;

R⁹ is independently selected at each occurrence from the group H, C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

R¹³ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)--, and heteroaryl(C₁₋₂ alkyl)--;

R^(13a) and R^(16a) are independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

R¹⁴ is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkyl, aryl(C₁₋₂ alkyl)--, and heteroaryl(C₁₋₂ alkyl)--;

R^(14a) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

R^(14b) is selected from the group C₁₋₄ alkyl, C₁₋₂ haloalkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₂ alkyl;

R¹⁵ is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group C₁₋₄ alkyl, Br, Cl, F, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

R^(15a) is independently selected at each occurrence from the group H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl;

R¹⁷, R¹⁸ and R¹⁹ are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

alternatively, in an NR¹⁷ R¹⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group R¹³, CO₂ R¹⁴, COR¹⁴ and SO₂ R¹⁴ ;

R^(17a) and R^(19a) are independently selected at each occurrence from the group H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl;

aryl is phenyl substituted with 1-4 substituents independently selected at each occurrence from the group C₁₋₄ alkyl, C₃₋₆ cycloalkyl, --OR¹⁷, Br, Cl, F, C₁₋₄ haloalkyl, --CN, --S(O)_(n) R^(l8), --COR¹⁷, --CO₂ R¹⁷, --NR¹⁵ COR¹⁷, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ ; and,

heteroaryl is independently selected at each occurence from the group pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 1-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, C₁₋₄ haloalkyl, --CN, --OR¹⁷, --S(O)_(m) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R CO₂ R^(14a), COR^(14a) and SO₂ R^(14a).

[2b] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

X is selected from the group O, S and a bond

R¹ is selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl and C₃₋₈ cycloalkyl-C₁₋₆ alkyl;

R¹ is substituted with 0-1 substituents selected from the group --CN, --CO₂ R^(13a), and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group --O--, --S(O)_(n) --, and --NR^(13a) --; R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, CF₃, --OR^(13a), --NR^(13a) R^(16a), C₁₋₂ alkoxy-C₁₋₂ -alkyl, and C₃₋₆ cycloalkyl which is substituted with 0-1 CH₃ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by --O--;

provided that R¹ is other than a cyclohexyl--(CH₂)₂ -- group;

R^(1a) is aryl and is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, and OCF₃, and 0-3 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, Br, Cl, F, CF₃, --CN, SCH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂ ;

R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, and indazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH (CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, SCH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂ CH₃, COCH₃ and SO₂ CH₃ ;

provided that R¹ is other than a --(CH₂)₁₋₄ -aryl or --(CH₂)₁₋₄ -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R² is selected from the group CH₃, CH₂ CH₃, CH(CH₃)₂, and CH₂ CH₂ CH₃ ;

R³ and R⁸ are independently selected at each occurrence from the group H, CH₃, CH₂ CH₃, CH(CH₃)₂, and CH₂ CH₂ CH₃ ;

aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, SCH₃, --SO₂ CH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂ ; and,

heteroaryl is independently selected at each occurence from the group pyridyl, indolyl, benzothienyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, and benzoxazolin-2-on-yl, each heteroaryl being substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, SCH₃, --SO₂ CH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂ CH₃, COCH₃ and SO₂ CH₃.

[2c] In a still more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is substituted C₁ ;

R¹ is substituted with 0-1 substituents selected from the group --CN, --CO₂ CH₃, and --CO₂ CH₂ CH₃ ;

R¹ is also substituted with 0-2 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, --(CH₂)₃ CH₃, --CH═CH₂, --CH═CH(CH₃), --CH═CH, --CH═C(CH₃), --CH₂ OCH₃, --CH₂ CH₂ OCH₃, F, CF₃, cyclopropyl, CH₃ -cyclopropyl, cyclobutyl, CH₃ -cyclobutyl, cyclopentyl, CH₃ -cyclopentyl;

R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂ CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, Br, Cl, F, CF₃, --CN, and SCH₃ ;

R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, and tetrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, OCH₃, OCH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, and SCH₃ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group CH₃, CO₂ CH₃, COCH₃ and SO₂ CH₃ ;

provided that R¹ is other than a --(CH₂)₁₋₄ -aryl or --(CH₂)₁₋₄ -heteroaryl wherein the aryl or heteroaryl group is substituted or unsubstituted;

R² is selected from the group CH₃, CH₂ OH₃, and CH(CH₃)₂ ;

R³, R⁷ and R⁸ are independently selected at each occurrence from the group H and CH₃ ;

aryl is phenyl substituted with 2-4 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, SCH₃, SO₂ CH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂ ; and,

heteroaryl is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, SCH₃, SO₂ CH₃, --NH₂, --NHCH₃, --N(CH₃)₂, --C(O)NH₂, --C(O)NHCH₃, and --C(O)N(CH₃)₂.

[2d] In a further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is substituted (cyclopropyl)-C₁ alkyl or (cyclobutyl)-C₁ alkyl;

R¹ is substituted with 0-1 --CN;

R¹ is also substituted with 0-1 substituents independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, --(CH₂)₃ CH₃, --CH═CH₂, --CH═CH(CH₃), --CH═CH, --CH═C(CH₃), --CH₂ OCH₃, --CH₂ CH₂ OCH₃, F, CF₃, cyclopropyl, and CH₃ -cyclopropyl;

R^(1a) is phenyl substituted with 0-1 substituents selected from OCH₃, OCH₂ CH₃, and OCF₃, and 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, Br, Cl, F, CF₃, --CN, and SCH₃ ;

R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, and pyrazolyl, each heteroaryl being substituted on 0-3 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, OCH₃, OCH₂ CH₃, OCF₃, Br, Cl, F, CF₃, --CN, and SCH₃.

[2e] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is (cyclopropyl)C₁ alkyl or (cyclobutyl)-C₁ alkyl substituted with 1 substituent independently selected at each occurrence from the group R^(1a), R^(1b), CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, --(CH₂)₃ CH₃, --CH═CH₂, --CH═CH(CH₃), --CH═CH, --CH═C(CH₃), --CH₂ OCH₃, --CH₂ CH₂ OCH₃, F, CF₃, cyclopropyl, and CH₃ -cyclopropyl;

R^(1a) is phenyl substituted with 0-2 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, Cl, F, and CF₃ ;

R^(1b) is heteroaryl and is selected from the group furanyl, thienyl, and isoxazolyl, each heteroaryl being substituted on 0-2 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, OCH₃, Cl, F, and CF₃.

[2f] In an even further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from the group (cyclopropyl)CH--CH₃, (cyclopropyl)CH--CH₂ CH₃, (cyclopropyl) CH--CH₂ OCH₃, (cyclopropyl) CH--CH₂ CH₂ CH₃, (cyclopropyl) CH--CH₂ CH₂ OCH₃, (cyclopropyl)₂ CH, phenyl(cyclopropyl)CH, furanyl(cyclopropyl)CH, thienyl(cyclopropyl)CH, isoxazolyl(cyclopropyl)CH, (CH₃ -furanyl)(cyclopropyl)CH, (cyclobutyl)CH--CH₃, (cyclobutyl)CH--CH₂ CH₃, (cyclobutyl)CH--CH₂ OCH₃, (cyclobutyl)CH--CH₂ CH₂ CH₃, (cyclobutyl)CH--CH₂ CH₂ OCH₃, (cyclobutyl)₂ CH, phenyl(cyclobutyl)CH, furanyl(cyclobutyl)CH, thienyl(cyclobutyl)CH, isoxazolyl(cyclobutyl)CH, and (CH₃ -furanyl)(cyclobutyl)CH;

[2g] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

D is phenyl substituted with 3-5 substituents independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH(CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, and CF₃.

[2h] In another further preferred embodiment, the present invention provides a novel compound of formula I, wherein:

D is pyridyl substituted on 2-4 carbon atoms with a substituent independently selected at each occurrence from the group CH₃, CH₂ CH₃, CH(CH₃)₂, CH₂ CH₂ CH₃, cyclopropyl, OCH₃, OCH₂ CH₃, OCH (CH₃)₂, OCH₂ CH₂ CH₃, OCF₃, Br, Cl, F, and CF₃.

[2i] In another preferred embodiment, R¹ is other than a cyclohexyl-(CH₂)₁, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group;

[2j] In another preferred embodiment, R¹ is other than an aryl-(CH₂)₁, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the aryl group is substituted or unsubstituted;

[2k] In another preferred embodiment, R¹ is other than a heteroaryl-(CH₂)₁, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the heteroaryl group is substituted or unsubstituted;

[2l] In another preferred embodiment, R¹ is other than a heterocyclyl-(CH₂)₁, 2, 3, 4, 5, 6, 7, 8, 9, or 10 -group, wherein the heterocyclyl group is substituted or unsubstituted.

[2m] In another preferred embodiment, when D is imidazole or triazole, R¹ is other than unsubstituted C₁, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linear or branched alkyl or C₃, 4, 5, 6, 7, or 8 cycloalkyl.

[2n] In another preferred embodiment, R^(1a) is not substituted with OR¹⁷.

[2o] In another preferred embodiment, the present invention provides a novel compound of formula I, wherein the compound is selected from:

1-(1-ethyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-ethyl)propyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-methyl)butyl-2-ethyl-4-(2,4,5-trichlorophenyl)-7-methyl-1H-benzimidazole,

1-(1-methyl)butyl-2-methyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-methyl)butyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-butyl)-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-carbmethoxy)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-carbmethoxy)ethyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-Dicyclopropyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-Dicyclopropyl)methyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1-cyclopropyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-6-methyl-1H-benzimidazole,

1-(1-phenyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-(1,1-diphenyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)benzimidazole,

1-(2-methyl)cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)-1H-benzimidazole,

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4,6-trichlorophenyl)-1H-benzimidazole,

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4-dichlorophenyl)-1H-benzimidazole

1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,

1-(1-cyclopropyl)butyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole,

1-(3-pentyl)-2-ethyl-4-(2,4-dimethyl-5-fluorophenyl)-1H-benzimidazole,

1-(2-pentyl)-2-ethyl-4-(2,4-dimethyl-5-fluorophenyl)-1H-benzimidazole,

1-(2-methyl)butyl-2-ethyl-4-(2,4-dichloro-5-fluorophenyl)-1H-benzimidazole,

1-cyclopentyl-2-ethyl-4-(2,4,6-trimethyl-3-pyridyl)-1H-benzimidazole,

In another embodiment, the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a method of treating psychiatric disorders and neurological diseases including affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in a mammal, comprising: administering to the mammal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.

The CRF antagonist compounds provided by this invention and labelled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. "Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counter-ion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused ring and Spiro compounds containing, for example, the above heterocycles.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Each of the references cited below are hereby incorporated herein by reference.

The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The novel benzimidazoles of Formulae (I) of this invention may be prepared by one of the general schemes outlined below (Schemes 1-2). Compounds of Formulae (I) of this invention may be prepared as shown in Scheme I. An appropriately substituted 2-nitroaniline (II) is temporarily protected as the acetamide affording compounds of formula (III). The acetate is shown as example and is not intended to limit the choice of protecting groups at this position. The acetamide formation is typically conducted in the presence of acetic anhydride, although acetyl chloride may also be utilized. The reaction may be conducted in a wide array of typically utilized organic solvents, however, methylene chloride is generally preferred. Subsequent nitration, most commonly with chilled fuming nitric acid, affords in excellent yield the dinitro acetamide (IV). Details for this transformation may be found in the classical teachings of Vivian, etal. (J. Org. Chem. 1950, 20, 797).

Formation of compounds of formula (V) proceeds by hydrolysis of the acetamido group (see Green, T. W., Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991, p.351) and functional group interconversion of the amine to the bromide via either a Sandmeyer reaction or Gatterman reaction via the intermediacy of the corresponding diazonium ion. One familiar in the art of organic synthesis will readily understand the optimal conditions necessary to effect this transformation, and may consult the text of March, J. (Advanced Organic Chemistry, John Wiley and Sons, Inc., New York, N.Y., 1985, p.570 and p.647).

Compounds of formula (V) are reduced to the diamines of formula (VI) under a wide variety of potentially optimal conditions known to those skilled in the art. One may also consult the guide of Larock, R. C. (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, VCH Publishers, Inc., New York, N.Y., 1989, p.411). The cyclized compounds of formula (VII) may be synthesized by treatment of diamines of formula (VI) with an ortho acid derivative of the formula (alkyl--O)₃ C--X--R² where alkyl is preferably methyl, ethyl or propyl. The cyclizations are preferably carried out in the presence of an acid catalyst such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid or an organic acid such as, but not limited to, propionic acid. The reactions are conducted at room temperature or optionally at elevated temperature up to boiling to effect loss of (alkyl--OH) from the reaction.

Treatment of compounds of formula (VII) with a base and a compound of formula R¹ -X wherein X represents a leaving group may afford the desired benzimidazole compounds of formula (VIII). Leaving groups may include, but are not limited to, bromo, chloro, iodo, cyano, alkoxy, methanesulfonyl, and p-toluenesulfonyl. Possible bases include, but are not limited to, the sodium, lithium or potassium bis(trimethylsilyl)amides, sodium or potassium hydride, alkyl lithiums and alkyl grignards and inorganic bases such as sodium, potassium and lithium hydroxide. The reactions are optionally conducted at room temperature or at elevated temperatures up to the boiling point of a cosolvent.

A wide variety of inert solvents may be employed, for example, dimethylformamide, dimethylsulfoxide, toluene, tetrahydrofuran, diethyl ether, and methylene chloride. The reactions may be successfully performed in glass reaction vessels or polypropylene wells, and one skilled in the art of organic chemistry will readily understand the optimal combinations of above conditions for effecting this transformation. Although regiomeric alkylation products are conceivable from tautomers of formula (VII), the experimental conditions taught herein will selectively provide the desired regiomer represented by compounds of formula (VIII). Alternatively, compounds of formula (VIII) may be formed under the classic conditions of the Mitsunobu reaction (Synthesis, 1980, p.1) from compounds of formula (VII) and an alcohol R¹ --OH.

Finally, the benzimidazoles of formula (I) may be formed from precursors of formula (VIII) by treatment with boronic acids of formula D-B(OH)₂ in the necessary presence of a palladium source, noteably Pd(OAc)₂ with the additives triphenyl-phosphine and sodium carbonate. The preferred solvent of the Suzuki coupling is dimethoxyethane, although other inert organic solvents such as diethyl ether, and tetrahydrofuran may also be employed. The reaction is effected at room temperature or at temperatures up to the boiling point of the solvent. One skilled in the art will understand optimized conditions as taught by Larsen, R. D. (J. Org. Chem. 1994, 54, 6391-6394).

Alternatively, the benzimidazoles of formula (I) may also be prepared according to Scheme 2. A similiar teaching also appears in EP 0812831 (vide supra). Thus, under conditions taught in Scheme 1, the aryl bromides of formula (IX) are coupled to reagents of formula D-B(OH)₂ to afford compounds of formula (X). For the preparation of compounds of formula (IX), one may refer to the art of Peet, etal. (J. Heterocyclic Chem. 1979, 16, 33-39) for details (R³ ═R⁷ ═R⁸ ═H). Hydrolysis of the carboalkoxy of compounds of formula (X) under conditions familiar to anyone in the art affords the acid derivatives of formula (XI) which are then subjected to a modified Curtius rearrangement (see March, J., Advanced Organic Chemistry, John Wiley and Sons, Inc., New York, N.Y., 1985, p.984) in the presence of diphenylphosphoryl azide and a trialkyl amine base in an inert solvent (ie. dry benzene, dry toluene). The reaction is preferrably refluxed for one hour, cooled and treated with t-butanol and heated for an additional 2-24 hours to effect incorporation of the t-butyl carbamate, providing compounds of formula (XII, PG═Boc).

Reduction of compounds of formula (XII) under a wide variety of methods known to those skilled in the art affords cleanly the aryl diamines of formula (XIII). Common reduction methods include hydrogenation in the presence of a catalyst such as Raney nickel (RaNi) or palladium on carbon (Pd/C) in an inert alcohol solvent (methanol, ethanol) or ethyl acetate. The reactions are optionally run under pressure and at elevated temperature (60° C.). Alternatively, and preferably, the reduction may be effected in exceptionally high yield by treatment of compounds of formula (XII) with sodium dithionite in the presence of ammonium hydroxide. One optimal solvent combination for this reduction is a mixture of dioxane/water (1:1).

Formation of compounds of formula (XIV) is achieved by a common reductive amination procedure employing compounds of formula (XIII) and the appropriate R¹ aldehydes and ketones. The reaction is preferably conducted under anhydrous conditions in the presence of a dehydrating agent (ie, sodium sulfate, magnesium sulfate) and acid catalyst (ie. hydrochloric acid, sulfuric acid, or acetic acid). Examples of suitable reducing agents which are intended to exemplify and not limit the invention are sodium triacetoxyborohydride and sodium cyanoborohydride. Compounds of formula (XIV) are then deprotected under common conditions (PG═Boc, see, Green, T. W. Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York, N.Y., 1991, p.328) to afford pre-cyclization compounds of formula (XV).

Finally, the desired benzimidazoles of formula (I) are readily afforded from compounds of formula (XV) as described in Scheme 1 for the formation of (I) from compounds of formula (VIII). ##STR4##

The following example is provided to describe the invention in further detail. The example, which sets forth the best mode presently contemplated for carrying out the invention, is intended to illustrate and not to limit the invention.

EXAMPLE 1 2-Ethyl-1-(1-ethyl-propyl)-4-(2,4,5-trichloro-phenyl)-1H-benzimidazole

Step A:

2'; 4', 5'-Trichloro-3-nitro-biphenyl-2-carboxylic acid methyl ester

Under a nitrogen atmosphere in 15 ml of anhydrous dimethoxyethane (DME) was dissolved 461 mg (1.76 mmol) triphenylphosphine. The reaction was evacuated and repressurized under nitrogen and stirred for 15 minutes at which point 98.55 mg of palladium acetate was added. The reaction was stirred for an additional 15 minutes at which point 1.10 g (4.88 mmol) of 2,4,5-trichlorophenylboronic acid was added. The reaction was stirred another 15 minutes at which time 1.14 g (4.39 mmol) of methyl 2-bromo-5-nitrobenzoate and 5 ml of 2N sodium carbonate were added. The reaction was evacuated and repressurized under nitrogen and heated to reflux for 18 hours at which time it was cooled, poured into 250 ml water, and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the crude product as a brown oil. The crude product was purified by column chromatography on silica gel (275 g) and eluted with 20% ethyl acetate in hexanes to afford 740 mg (47%) of the title compound.

¹ H NMR (CDCl₃) 8.22 (dd, 1H, J=7 Hz, 1 Hz), 7.61 (m, 3H), 7.41 (s, 1H), 3.74 (s, 3H).

Step B:

2', 4', 5'-Trichloro-3-nitro-biphenyl-2-carboxylic acid

Under a nitrogen atmosphere was combined 735 mg (2.03 mmol) of the title compound Step A, 5 ml of tetrahydrofuran (THF), 3 ml of methanol, and 5 ml of water. To this solution was added 320 mg (8 mmol) of freshly powdered sodium hydroxide and the resulting solution was heated to reflux for 90 minutes. The reaction was cooled and concentrated in vacuo, diluted with 40 ml water and extracted with ethyl acetate (1×25 ml). After separation the aqueous layer was acidified to pH <2 with 6.25N hydrochloric acid (HCl) and extracted with ethyl acetate (3×25 ml). The combined organic extracts from the acidified water layer were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield 700 mg (100%) of the title compound.

¹ H NMR (CDCl₃) 8.23 (dd, 1H, J=7 Hz, 1 Hz), 7.61 (m, 3H), 7.26 (s, 1H). HRMS (M-H)⁻ calcd for C₁₆ H₅ Cl₃ N₁ O 343.9284, found 343.9297.

Step C:

(2', 4', 5'-Trichloro-3-nitro-biphenyl-2-yl)-carbamic acid tert-butyl ester

Under a nitrogen atmosphere in 20 ml of anhydrous benzene was combined 700 mg (2.03 mmol) of the title compound in Step B and 2.03 ml of triethylamine (TEA). To this solution was added 437 ml (2.03 mmol) of diphenylphosphoryl azide, and the resulting solution was heated to reflux for 1 hour. After completion the reaction mixture was cooled and 301 mg (4.06 mmol) of t-butanol was added, and the solution was heated to reflux for an additional 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (200 g) and eluted using 20% ethyl acetate in hexanes to afford 502 mg (59%) of the title compound as a light yellow solid.

¹ H NMR (CDCl₃) 8.06 (dd, 1H, J=7 Hz, 1.5 Hz), 7.62 (s, 1H), 7.49 (m, 3H), 1.28 (s, 9H). HRMS (M-H)⁻ calcd for C₁₇ H₁₄ Cl₃ N₂ O 415.0019, found 415.0014.

Step D:

(3-Amino-2',4',5'-trichloro-biphenyl-2-yl)-carbamic acid tert-butyl ester

To 12 ml of a 1:1 solution of dioxane and water was added 500 mg (1.2 mmol) of the title compound in Step C and 0.6 ml of concentrated ammonium hydroxide. To this suspension was added 1.67 g (9.6 mmol) of sodium dithionite. The reaction mixture was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The resulting oil was dissolved in 1:1 ethyl acetate and water and the layers separated. The aqueous layer was extracted with ethyl acetate (2×25 ml) and the combined organic extracts dried over magnesium sulfate, filtered, and evaporated to yield 536.6 mg (100%) of the title compound as a beige solid. 1H NMR (DMSO d₆) 8.00 (br s, 1H), 7.80 (s, 1H), 7.40 (s, 1H), 6.98 (t, 1H, J=8 Hz), 6.74 (d, 1H, i═7.5 Hz), 6.43 (d, 1H, J=7 Hz), 1.16 (br s, 9H). HRMS (M+H)⁺ calcd for C₁₇ H18Cl₃ N₂ O₂ 387.0433, found 387.0421.

Step E:

[3(1-Ethyl-propylamino)-2',4',5'-trichloro-binhenyl-2-yl]-carbamic acid tert-butyl ester

Under a nitrogen atmosphere was combined 5 ml of acetic acid, 232 mg (0.6 mmol) of the title compound in Step D and 122 ml of 3-pentanone. To this solution was added 853 mg (6 mmol) of sodium sulfate. The solution was stirred at room temperature for 25 minutes at which time 153 mg (0.72 mmol) of sodiumtriacetoxyborohydride was added. The reaction was allowed to stir at room temperature for an additional 1 hour and then quenched with aqueous sodium carbonate (100 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to afford the crude product as a light brown oil. The crude product was purified by column chromatography on silica gel (30 g) and eluted with 20% ethyl acetate in hexanes to afford 171 mg (62%) of the title compound.

¹ H NMR (CDCl₃) 7.55 (s, 1H), 7,41 (br s, 1H), 7.21 (t, 1H, J=8 Hz), 6.71 (d, 1H, J=8 Hz), 6.46 (d, 1H, J=7 Hz), 3.32 (m, 1H), 1.58 (m, 4H), 1.3 (S, 9H), 0.9 (m, 6H). HRMS (M+H)⁺ calcd for C₂₂ H₂₈ Cl₃ N₂ O₂ 457.1216, found 457.1211.

Step F:

N-3-(1-Ethyl-propylamino)-2',4',5'-trichloro-biphenyl-2,3-diamine

Under a nitrogen atmosphere was dissolved 171 mg (0.37 mmol) of the title compound in Step E in 1 ml of dichloromethane and the resulting solution chilled to 0° C. Trifluoroacetic acid (12 ml) was added dropwise over 4 minutes and the reaction stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stir for an additional 1 hour. Reaction was then evaporated in vacuo and the residual oil taken up in dichloromethane. The organic layer was washed with 1N sodium hydroxide (1×25 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×25 ml) and the combined organic extracts dried over sodium sulfate filtered and evaporated to yield 129 mg (99%) of the product as a brown oil.

.sup. 1H NMR (CDCl₃) 7.62 (S, 1H), 7.46 (S, 1H), 6.86 (t, 1H, J=8 Hz), 6.69 (d, 1H, J=7 Hz), 6.48 (d, 1H, J=6 Hz), 3.25 (m, 1H), 1.60 (m, 4H), 0.95 (m, 6H). HRMS (M+H)⁺ calcd for C₁₇ H₂₀ Cl₃ N₂ 357.0692, found 357.0693.

Step G:

2-Ethyl-1-(1-ethyl-propyl)-4-(2,4,5-trichloro-phenyl)-1H-benzimidazole

Under a nitrogen atmosphere was combined 129 mg (0.36 mmol) of the title compound of Step F in 5 ml of triethylorthopropionate. To the resulting solution was added 2 drops of concentrated hydrochloric acid. The reaction was allowed to stir at room temperature for 8 hours and then poured into 100 ml of water. The reaction was extracted with ethyl acetate (4×20 ml) and the combined organic extracts dried over sodium sulfate, filtered, and evaporated to yield the crude product as a light brown crystal. The crude product was purified by column chromatography on silica gel (20 g) and eluted with 20% ethyl acetate in hexanes to yield 101 mg (71%) of the title compound as a brown solid. M.P. =150.0-151.5° C.; .sup. 1H NMR (CDCl₃) 7.72 (s, 1H), 7.61 (s, 1H), 7.52 (m, 1H), 7.20 (m, 2H), 4.10 (m, 1H), 2.92 (q, 2H, J=8 Hz), 2.18 (m, 2H), 2.05 (m, 2H), 1.38 (t, 3H, J=8 Hz), 0.83 (t, 6H, J=7.5 Hz); HRMS calc. for C₂₀ H₂₁ N₂ Cl₃ : (M+H)⁺ 395.0849, Found 395.0846; Anal Calcd for C₂₀ H₂₁ N₂ Cl₃ : C, 60.70; H, 5.358; N, 7.088. Found C, 60.40; H, 5.46; N, 6.75.

The foregoing tables contain further examples which are meant to be illustrative of the present invention, and not to be taken as limiting thereof.

                                      TABLE 1                                      __________________________________________________________________________       #STR5##                                                                         -                                                                           Ex.                                                                               R.sup.1    X   R.sup.2                                                                             R.sup.3                                                                            R.sup.7                                                                           R.sup.8                                                                            Mass Spec                                    __________________________________________________________________________     1  CH(CH.sub.2 CH.sub.3).sub.2                                                               CH.sub.2                                                                           CH.sub.3                                                                            H   H  H   395.09                                         2 CH(CH.sub.2 CH.sub.3).sub.2 CH.sub.2 CH.sub.3 CH.sub.3 H H                   3 CH(CH.sub.2 CH.sub.3).sub.2 CH.sub.2 CH.sub.3 H CH.sub.3 H                   4 CH(CH.sub.2 CH.sub.3).sub.2 CH.sub.2 H H H H                                 5 CH(CH.sub.2 CH.sub.3).sub.2 O CH.sub.3 H H H                                 6 CH(CH.sub.2 CH.sub.3).sub.2 O CH.sub.3 H H CH.sub.3                          7 CH(CH.sub.2 CH.sub.3).sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H H                 8 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H CH.sub.3 H        9 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 H H H H                      10 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 O CH.sub.3 H H H                     11 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 O CH.sub.3 H H CH.sub.3                                               12 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2                                        CH.sub.3 H H H                                 13 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                 14 CH.sub.2 CH(CH.sub.2 CH.sub.3).sub.2 CH.sub.2 CH.sub.3 H H H                                                 15 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                        CH.sub.2 CH.sub.3 H H H                       16 CH(CO.sub.2 CH.sub.3)CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                                               17 CH(CO.sub.2 CH.sub.2 CH.sub.3)CH.sub                                       .3 CH.sub.2 CH.sub.3 H H H                     18 CH(COCH.sub.3)CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                     19 CH(COPh)CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                           20 CH.sub.2 CH.sub.2 C.tbd.CCH.sub.3 CH.sub.2 CH.sub.3 H H H                   21 CH(cyclo-Pr).sub.2 CH.sub.2 CH.sub.3 H H H                                  22 CH(cyclo-Pr).sub.2 CH.sub.2 CH.sub.3 CH.sub.3 H H                           23 CH(cyclo-Pr).sub.2 CH.sub.2 CH.sub.3 H CH.sub.3 H                           24 CH(cyclo-Pr).sub.2 CH.sub.2 H H H H                                         25 CH(cyclo-Pr).sub.2 CH.sub.2 H H CH.sub.3 H                                  26 CH(cyclo-Pr).sub.2 O CH.sub.3 H H CH.sub.3                                  27 CH(cyclo-Pr).sub.2 O CH.sub.3 H H H                                         28 CH(cyclo-Pr).sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H H H                         29 CH.sub.2 cyclopropyl CH.sub.2 CH.sub.3 H H H                                30 CH.sub.2 cyclopropyl CH.sub.2 CH.sub.3 CH.sub.3 H H                         31 CH.sub.2 cyclopropyl CH.sub.2 CH.sub.3 H CH.sub.3 H                         32 CH(Et)(c-Pr) CH.sub.2 CH.sub.3 H H H                                        33 CH(Et)(c-Pr) CH.sub.2 CH.sub.3 CH.sub.3 H H                                 34 CH(Et)(c-Pr) CH.sub.2 CH.sub.3 H CH.sub.3 H                                 35 CH(Et)(c-Pr) CH.sub.2 H H H H                                               36 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                                                 37 CH.sub.2 CH.sub.2 OCH.sub.2                                                CH.sub.3 CH.sub.2 H H H H                      38 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 O CH.sub.3 H H H                       39 cyclopentyl CH.sub.2 CH.sub.3 H H H                                         40 cyclopentyl CH.sub.2 CH.sub.3 Me H H                                        41 cyclohexyl CH.sub.2 CH.sub.3 H H H                                          42 cyclohexyl CH.sub.2 CH.sub.3 H Me H                                         43 CH.sub.2 Ph CH.sub.2 CH.sub.3 H H H                                         44 CH.sub.2 Ph O CH.sub.3 H H H                                                45 CH(Ph)CH.sub.2 CH.sub.3 CH.sub.2 CH.sub.3 H H H                             46 CH(Ph).sub.2 CH.sub.2 CH.sub.3 H H H                                        47 CH.sub.2 -(2-chloroPh) CH.sub.2 CH.sub.3 H H H                              48 CH.sub.2 -(4-chloroPh) CH.sub.2 CH.sub.3 H H H                              49 CH.sub.2 -(4-MeO--Ph) CH.sub.2 CH.sub.3 H H H                               50 CH.sub.2 -(4-CF.sub.3 O--Ph) CH.sub.2 CH.sub.3 H H H                      __________________________________________________________________________

                  TABLE 2                                                          ______________________________________                                           #STR6##                                                                        Ex.    R.sup.1        D                                                      ______________________________________                                         1    cyclopentyl    2,4,6-trimethylphenyl                                        2 cyclohexyl 2,4,6-trimethylphenyl                                             3 2-methyl(c-pentyl) 2,4,6-trimethylphenyl                                     4 benzyl 2,4,6-trimethylphenyl                                                 5 2-chlorobenzyl 2,4,6-trimethylphenyl                                         6 4-chlorobenzyl 2,4,6-trichlorophenyl                                         7 CH(cyclopropyl).sub.2 2,4,6-trichlorophenyl                                  8 4-fluorobenzyl 2,4-dichlorophenyl                                            9 CH(cyclopropyl).sub.2 2-chloro-4-bromophenyl                                 10 4-bromobenzyl 2-chloro-4-bromophenyl                                        11 4-methoxybenzyl 2-chloro-4-bromophenyl                                      12 CH(cyclopropyl).sub.2 2-thiomethyl-4-bromophenyl                            13 CH(cyclopropyl).sub.2 2-methyl-4-methoxyphenyl                              14 CH(c-Pr)CH.sub.2 CH.sub.2 CH.sub.3 2-methyl-4-methoxyphenyl                 15 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 2,4-dimethyl-5-fluorophenyl                                16 CH(CH.sub.2 CH.sub.3).sub.2 2,4-dimethyl-5-fluorop                         henyl                                                        17 CH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3 2,4-dimethyl-5-fluorophenyl                             18 CH.sub.2 CH(CH.sub.3)CH.sub.2 CH.sub.3 2,4-dichlor                         o-5-fluorophenyl                                             19 CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 2,4-dichloro-5-fluorophenyl                               20 CH(Ph)(c-Pr) 2-bromo-4-dimethylaminophenyl                                  21 CH(4-F--Ph)(c-Pr) 2-methyl-4-dimethylaminophenyl                            22 cyclopentyl 2,4,6-trimethyl-3-pyridyl                    23 cyclohexyl 2,4,6-trimethyl-3-pyridyl                                        24 2-methyl(c-pentyl) 2,4,6-trimethyl-3-pyridyl                                25 benzyl 2,4,6-trimethyl-3-pyridyl                                            26 CH(CH.sub.2 CH.sub.3).sub.2 2,4,6-trimethyl-3-pyridyl                       27 cyclopentyl 2,4-dimethyl-3-pyridyl                                          28 cyclohexyl 4,6-dimethyl-3-pyridyl                                           29 2-methyl(c-pentyl) 2,4-dimethoxy-3-pyridyl                                  30 benzyl 2-methyl-4-dimethylamino-3-pyridyl                                   31 2-methyl(c-pentyl) 6-methyl-4-dimethylamino-3-pyridyl                       32 benzyl 2,4,6-trimethyl-3,5-pyrimidyl                                        33 CH(CH.sub.2 CH.sub.3).sub.2 2,4-dimethyl-3,5-pyrimidyl                      34 cyclopentyl 4-isopropyl-2-furanyl                                           35 cyclohexyl 5-isopropyl-2-furanyl                                            36 2-methyl(c-pentyl) 4-isopropyl-2-thiophenyl                                 37 benzyl 5-isopropyl-2-thiophenyl                                           ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                           #STR7##                                                                         - a.sub.1 R.sup.2 X = CH.sub.3 O                                              a.sub.2 R.sup.2 X = CH.sub.3 S                                                 a.sub.3 R.sup.2 X = Me                                                         a.sub.4 R.sup.2 X = Et                                                         a.sub.5 R.sup.2 X = n-Pr                                                        -                                                                             #STR8##                                                                         - b.sub.1 R.sup.2 X = CH.sub.3 O                                              b.sub.2 R.sup.2 X = CH.sub.3 S                                                 b.sub.3 R.sup.2 X = Me                                                         b.sub.4 R.sup.2 X = Et                                                         b.sub.5 R.sup.2 X = n-Pr                                                        -                                                                             #STR9##                                                                         - c.sub.1 R.sup.2 X = CH.sub.3 O                                              c.sub.2 R.sup.2 X = CH.sub.3 S                                                 c.sub.3 R.sup.2 X = Me                                                         c.sub.4 R.sup.2 X = Et                                                         c.sub.5 R.sup.2 X = n-Pr                                                        -                                                                             #STR10##                                                                        - d.sub.1 R.sup.2 X = CH.sub.3 O                                              d.sub.2 R.sup.2 X = CH.sub.3 S                                                 d.sub.3 R.sup.2 X = Me                                                         d.sub.4 R.sup.2 X = Et                                                         d.sub.5 R.sup.2 X = n-Pr                                                     ______________________________________                                           Ex. #   R.sup.1           D                                                  ______________________________________                                            1 (cPr).sub.2 CH 2-Cl-4-MeO-phenyl                                             2 phenyl(cPr)CH 2-Cl-4-MeO-phenyl                                              3 2-furanyl(cPr)CH 2-Cl-4-MeO-phenyl                                           4 3-furan(cPr)CH 2-Cl-4-MeO-phenyl                                             5 2-thienyl(cPr)CH 2-Cl-4-MeO-phenyl                                           6 3-thienyl(cPr)CH 2-Cl-4-MeO-phenyl                                           7 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-phenyl                                        8 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-MeO-phenyl                             9 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-MeO-phenyl                          10 cPr-CH(CH.sub.3) 2-Cl-4-MeO-phenyl                                          11 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-phenyl                               12 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-phenyl                      13 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-phenyl                              14 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-phenyl                     15 (cBu).sub.2 CH 2-Cl-4-MeO-phenyl                                            16 phenyl(cBu)CH 2-Cl-4-MeO-phenyl                                             17 2-furanyl(cBu)CH 2-Cl-4-MeO-phenyl                                          18 3-furan(cBu)CH 2-Cl-4-MeO-phenyl                                            19 2-thienyl(cBu)CH 2-Cl-4-MeO-phenyl                                          20 3-thienyl(cBu)CH 2-Cl-4-MeO-phenyl                                          21 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-phenyl                                       22 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-MeO-phenyl                            23 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-MeO-phenyl                         24 cBu-CH(CH.sub.3) 2-Cl-4-MeO-phenyl                                          25 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-phenyl                               26 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-phenyl                      27 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-phenyl                              28 1-cBu-CH (CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-phenyl                    29 (cPr).sub.2 CH 2-Cl-4-CF.sub.3 -phenyl                                      30 phenyl(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                       31 2-furanyl(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                    32 3-furan(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                      33 2-thienyl(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                    34 3-thienyl(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                    35 2-isoxazolyl(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                                 36 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                      37 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-CF.sub.3 -phenyl                   38 cPr-CH(CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                    39 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                         40 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                           41 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CF.su                                 b.3 -phenyl                                           42 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                          43 (cBu).sub.2 CH 2-Cl-4-CF.sub.3 -phenyl                                      44 phenyl(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                                       45 2-furanyl(cBu)CH 2-Cl-4-CF.sub.3 -phenyl         46 3-furan(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                                      47 2-thienyl(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                                    48 3-thienyl(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                                    49 2-isoxazolyl(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                                 50 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                      51 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-CF.sub.3 -phenyl                   52 cBu-CH(CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                    53 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                         54 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                           55 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CF.su                                 b.3 -phenyl                                           56 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CF.sub.3 -phenyl                                          57 (cPr).sub.2 CH 2,4-diCl-phenyl                   58 phenyl(cPr)CH 2,4-diCl-phenyl                                               59 2-furanyl(cPr)CH 2,4-diCl-phenyl                                            60 3-furan(cPr)CH 2,4-diCl-phenyl                                              61 2-thienyl (cPr)CH 2,4-diCl-phenyl                                           62 3-thienyl(cPr)CH 2,4-diCl-phenyl                                            63 2-isoxazolyl(cPr)CH 2,4-diCl-phenyl                                         64 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCl-phenyl                              65 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCl-phenyl                           66 cPr-CH(CH.sub.3) 2,4-diCl-phenyl                                            67 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCl-phenyl                                 68 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-phenyl                        69 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-phenyl                                70 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-phenyl                       71 (cBu).sub.2 CH 2,4-diCl-phenyl                                              72 phenyl(cBu)CH 2,4-diCl-phenyl                                               73 2-furanyl(cBu)CH 2,4-diCl-phenyl                                            74 3-furan(cBu)CH 2,4-diCl-phenyl                                              75 2-thienyl(cBu)CH 2,4-diCl-phenyl                                            76 3-thienyl(cBu)CH 2,4-diCl-phenyl                                            77 2-isoxazolyl(cBu)CH 2,4-diCl-phenyl                                         78 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCl-phenyl                              79 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCl-phenyl                           80 cBu-CH(CH.sub.3) 2,4-diCl-phenyl                                            81 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCl-phenyl                                 82 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-phenyl                        83 1-cBu-CH (CH.sub.2 OCH.sub.3) 2,4-diCl-phenyl                               84 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-phenyl                       85 (cPr).sub.2 CH 2,5-diCl-phenyl                                              86 phenyl(cPr)CH 2,5-diCl-phenyl                                               87 2-furanyl(cPr)CH 2,5-diCl-phenyl                                            88 3-furan(cPr)CH 2,5-diCl-phenyl                                              89 2-thienyl(cPr)CH 2,5-diCl-phenyl                                            90 3-thienyl(cPr)CH 2,5-diCl-phenyl                                            91 2-isoxazolyl(cPr)CH 2,5-diCl-phenyl                                         92 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,5-diCl-phenyl                              93 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,5-diCl-phenyl                           94 cPr-CH(CH.sub.3) 2,5-diCl-phenyl                                            95 1-cPr-CH(CH.sub.2 CH.sub.3) 2,5-diCl-phenyl                                 96 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCl-phenyl                        97 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,5-diCl-phenyl                                98 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCl-phenyl                       99 (cBu).sub.2 CH 2,5-diCl-phenyl                                             100 phenyl(cBu)CH 2,5-diCl-phenyl                                              101 2-furanyl(cBu)CH 2,5-diCl-phenyl                                           102 3-furan(cBu)CH 2,5-diCl-phenyl                                             103 2-thienyl (cBu)CH 2,5-diCl-phenyl                                          104 3-thienyl(cBu)CH 2,5-diCl-phenyl                                           105 2-isoxazolyl(cBu)CH 2,5-diCl-phenyl                                        106 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,5-diCl-phenyl                             107 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,5-diCl-phenyl                          108 cBu-CH(CH.sub.3) 2,5-diCl-phenyl                                           109 1-cBu-CH(CH.sub.2 CH.sub.3) 2,5-diCl-phenyl                                110 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCl-phenyl                       111 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,5-diCl-phenyl                               112 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCl-phenyl                      113 (cPr).sub.2 CH 2-Cl-4-CF.sub.3 O-phenyl                                    114 phenyl(cPr) CH 2-Cl-4-CF.sub.3 O-phenyl                                    115 2-furanyl(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                                  116 3-furan(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                                    117 2-thienyl(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                                  118 3-thienyl(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                                  119 2-isoxazolyl(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                               120 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                    121 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-CF.sub.3 O-phenyl                 122 cPr-CH(CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                  123 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                       124 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                         125 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CF.su                                 b.3 O-phenyl                                         126 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                        127 (cBu).sub.2 CH 2-Cl-4-CF.sub.3 O-phenyl                                    128 phenyl(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                                     129 2-furanyl(cBu)CH 2-Cl-4-CF.sub.3                                          O-phenyl                                             130 3-furan(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                                    131 2-thienyl(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                                  132 3-thienyl(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                                  133 2-isoxazolyl(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                               134 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                    135 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-CF.sub.3 O-phenyl                 136 cBu-CH(CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                  137 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                       138 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                         139 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CF.su                                 b.3 O-phenyl                                         140 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CF.sub.3 O-phenyl                                        141 (cPr).sub.2 CH 2-Cl-4-CH.sub.3 -phenyl                                     142 phenyl(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                                      143 2-furanyl(cPr)CH 2-Cl-4-CH.sub.3 -phenyl        144 3-furan(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                                     145 2-thienyl(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                                   146 3-thienyl(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                                   147 2-isoxazoly1(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                                148 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                     149 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-CH.sub.3 -phenyl                  150 cPr-CH(CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                   151 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                        152 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                          153 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CH.su                                 b.3 -phenyl                                          154 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                         155 (cBu).sub.2 CH 2-Cl-4-CH.sub.3 -phenyl                                     156 phenyl(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                                      157 2-furanyl(cBu)CH 2-Cl-4-CH.sub.3 -phenyl        158 3-furan(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                                     159 2-thienyl(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                                   160 3-thienyl(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                                   161 2-isoxazolyl(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                                162 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                     163 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-CH.sub.3 -phenyl                  164 cBu-CH(CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                   165 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                        166 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                          167 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CH.su                                 b.3 -phenyl                                          168 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CH.sub.3 -phenyl                                         169 (cPr).sub.2 CH 2-Cl-4-CN-phenyl                 170 phenyl(cPr)CH 2-Cl-4-CN-phenyl                                             171 2-furanyl(cPr)CH 2-Cl-4-CN-phenyl                                          172 3-furan(cPr)CH 2-Cl-4-CN-phenyl                                            173 2-thienyl(cPr)CH 2-Cl-4-CN-phenyl                                          174 3-thienyl(cPr)CH 2-Cl-4-CN-phenyl                                          175 2-isoxazolyl(cPr)CH 2-Cl-4-CN-phenyl                                       176 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-CN-phenyl                            177 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-CN-phenyl                         178 cPr-CH(CH.sub.3) 2-Cl-4-CN-phenyl                                          179 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CN-phenyl                               180 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CN-phenyl                      181 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CN-phenyl                              182 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CN-phenyl                     183 (cBu).sub.2 CH 2-Cl-4-CN-phenyl                                            184 phenyl(cBu)CH 2-Cl-4-CN-phenyl                                             185 2-furanyl(cBu)CH 2-Cl-4-CN-phenyl                                          186 3-furan(cBu)CH 2-Cl-4-CN-phenyl                                            187 2-thienyl(cBu)CH 2-Cl-4-CN-phenyl                                          188 3-thienyl(cBu)CH 2-Cl-4-CN-phenyl                                          189 2-isoxazolyl(cBu)CH 2-Cl-4-CN-phenyl                                       190 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-CN-phenyl                            191 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-CN-phenyl                         192 cBu-CH(CH.sub.3) 2-Cl-4-CN-phenyl                                          193 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CN-phenyl                               194 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CN-phenyl                      195 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CN-phenyl                              196 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CN-phenyl                     197 (cPr).sub.2 CH 2-CF.sub.3 -4-Cl-phenyl                                     198 phenyl(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                                      199 2-furanyl(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                                   200 3-furan(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                                     201 2-thienyl(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                                   202 3-thienyl(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                                   203 2-isoxazolyl(cPr)CH 2-CF.sub.3 -4-Cl-pheny1                                204 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                     205 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CF.sub.3 -4-Cl-phenyl                  206 cPr-CH(CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                   207 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                        208 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                          209 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-Cl-phenyl                                         210 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                         211 (cBu).sub.2 CH 2-CF.sub.3 -4-Cl-phenyl                                     212 phenyl(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                                      213 2-furanyl(cBu)CH 2-CF.sub.3 -4-Cl-phenyl        214 3-furan(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                                     215 2-thienyl(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                                   216 3-thienyl(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                                   217 2-isoxazolyl(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                                218 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                     219 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CF.sub.3 -4-Cl-phenyl                  220 cBu-CH(CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                   221 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                        222 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                          223 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-Cl-phenyl                                         224 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-Cl-phenyl                                         225 (cPr).sub.2 CH 2-CF.sub.3 -4-MeO-phenyl                                    226 phenyl(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                                     227 2-furanyl(cPr)CH 2-CF.sub.3 -4-MeO-phenyl       228 3-furan(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                                    229 2-thienyl(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                                  230 3-thienyl(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                                  231 2-isoxazolyl(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                               232 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                    233 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CF.sub.3 -4-MeO-phenyl                 234 cPr-CH(CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                  235 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                       236 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                         237 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-MeO-phenyl                                        238 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                        239 (cBu).sub.2 CH 2-CF.sub.3 -4-MeO-phenyl                                    240 phenyl(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                                     241 2-furanyl(cBu)CH 2-CF.sub.3 -4-MeO-phenyl       242 3-furan(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                                    243 2-thienyl(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                                  244 3-thienyl(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                                  245 2-isoxazolyl(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                               246 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                    247 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CF.sub.3 -4-MeO-phenyl                 248 cBu-CH(CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                  249 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                       250 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                         251 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-MeO-phenyl                                        252 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-MeO-phenyl                                        253 (cPr).sub.2 CH 2-CF.sub.3 -4-n-PrO-phenyl       254 phenyl(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                   255 2-furanyl(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                256 3-furan(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                  257 2-thienyl(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                258 3-thienyl(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                259 2-isoxazolyl(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                             260 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                  261 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CF.sub.3 -4-n-PrO-phenyl                                          262 cPr-CH(CH.sub.3) 2-CF.sub.3 -4-n-PrO-phen                                 yl                                                   263 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                     264 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                                       265 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-n-PrO-phenyl                                      266 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                                      267 (cBu).sub.2 CH 2-CF.sub.3 -4-n-PrO-phenyl       268 phenyl(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                   269 2-furanyl(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                270 3-furan(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                  271 2-thienyl(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                272 3-thienyl(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                273 2-isoxazolyl(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                             274 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                  275 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CF.sub.3 -4-n-PrO-phenyl                                          276 cBu-CH(CH.sub.3) 2-CF.sub.3 -4-n-PrO-phen                                 yl                                                   277 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                     278 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                                       279 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-n-PrO-phenyl                                      280 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-n-PrO-phenyl                                      281 (cPr).sub.2 CH 2,4-diCF.sub.3 -phenyl                                      282 phenyl(cPr)CH 2,4-diCF.sub.3 -phenyl                                       283 2-furanyl(cPr)CH 2,4-diCF.sub.3 -phenyl                                    284 3-furan(cPr)CH 2,4-diCF.sub.3 -phenyl                                      285 2-thienyl(cPr)CH 2,4-diCF.sub.3 -phenyl                                    286 3-thienyl(cPr)CH 2,4-diCF.sub.3 -phenyl                                    287 2-isoxazolyl(cPr)CH 2,4-diCF.sub.3                                        -phenyl                                              288 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCF.sub.3 -phenyl                      289 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCF.sub.3 -phenyl                   290 cPr-CH(CH.sub.3) 2,4-diCF.sub.3 -phenyl                                    291 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCF.sub.3 -phenyl                         292 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCF.sub.3 -phenyl                                           293 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCF.sub                                 .3 -phenyl                                           294 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCF.sub.3 -phenyl                                          295 (cBu).sub.2 CH 2,4-diCF.sub.3 -phenyl                                      296 phenyl(cBu)CH 2,4-diCF.sub.3 -phenyl                                       297 2-furanyl(cBu)CH 2,4-diCF.sub.3 -phenyl                                    298 3-furan(cBu)CH 2,4-diCF.sub.3 -phenyl                                      299 2-thienyl(cBu)CH 2,4-diCF.sub.3 -phenyl                                    300 3-thienyl(cBu)CH 2,4-dieF3-phenyl                                          301 2-isoxazolyl(cBu)CH 2,4-diCF.sub.3                                        -phenyl                                              302 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCF.sub.3 -phenyl                      303 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCF.sub.3 -phenyl                   304 cBu-CH(CH.sub.3) 2,4-diCF.sub.3 -phenyl                                    305 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCF.sub.3 -phenyl                         306 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCF.sub.3 -phenyl                                           307 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diCF.sub                                 .3 -phenyl                                           308 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCF.sub.3 -phenyl                                          309 (cPr).sub.2 CH 2-CF.sub.3 -4-F-phenyl                                      310 phenyl(cPr)CH 2-CF.sub.3 -4-F-phenyl                                       311 2-furanyl(cPr)CH 2-CF.sub.3 -4-F-phenyl                                    312 3-furan(cPr)CH 2-CF.sub.3 -4-F-phenyl                                      313 2-thienyl(cPr)CH 2-CF.sub.3 -4-F-phenyl                                    314 3-thienyl(cPr)CH 2-CF.sub.3 -4-F-phenyl                                    315 2-isoxazolyl(cPr)CH 2-CF.sub.3 -4-F-pheny                                 l                                                    316 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CF.sub.3 -4-F-phenyl                      317 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CF.sub.3 -4-F-phenyl                   318 cPr-CH(CH.sub.3) 2-CF.sub.3 -4-F-phenyl                                    319 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-F-phenyl                         320 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-F-phenyl                                           321 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-F-phenyl                                          322 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-F-phenyl                                          323 (cBu).sub.2 CH 2-CF.sub.3 -4-F-phenyl                                      324 phenyl(cBu)CH 2-CF.sub.3 -4-F-phenyl                                       325 2-furanyl(cBu)CH 2-CF.sub.3 -4-F-phenyl                                    326 3-furan(cBu)CH 2-CF.sub.3 -4-F-phenyl                                      327 2-thienyl(cBu)CH 2-CF.sub.3 -4-F-phenyl                                    328 3-thienyl(cBu)CH 2-CF.sub.3 -4-F-phenyl                                    329 2-isoxazolyl(cBu)CH 2-CF.sub.3 -4-F-pheny                                 l                                                    330 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CF.sub.3 -4-F-phenyl                      331 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CF.sub.3 -4-F-phenyl                   332 cBu-CH(CH.sub.3) 2-CF.sub.3 -4-F-phenyl                                    333 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-F-phenyl                         334 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CF.sub.3 -4-F-phenyl                                           335 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CF.sub.3                                   -4-F-phenyl                                          336 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CF.sub.3 -4-F-phenyl                                          337 (cPr).sub.2 CH 2-CH.sub.3 -4-Cl-pheriyl                                    338 phenyl(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                                      339 2-furanyl(cPr)CH 2-CH.sub.3 -4-Cl-phenyl        340 3-furan(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                                     341 2-thienyl(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                                   342 3-thienyl(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                                   343 2-isoxazolyl(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                                344 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                     345 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CH.sub.3 -4-Cl-phenyl                  346 cPr-CH(CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                   347 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                        348 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                          349 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-Cl-phenyl                                         350 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                         351 (cBu).sub.2 CH 2-CH.sub.3 -4-Cl-phenyl                                     352 phenyl(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                                      353 2-furanyl(cBu)CH 2-CH.sub.3 -4-Cl-phenyl        354 3-furan(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                                     355 2-thienyl(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                                   356 3-thienyl(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                                   357 2-isoxazolyl(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                                358 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                     359 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CH.sub.3 -4-Cl-phenyl                  360 cBu-CH(CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                   361 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                        362 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                          363 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-Cl-phenyl                                         364 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-Cl-phenyl                                         365 (cPr).sub.2 CH 2-CH.sub.3 -4-MeO-phenyl                                    366 phenyl(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                                     367 2-furanyl(cPr)CH 2-CH.sub.3 -4-MeO-phenyl       368 3-furan(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                                    369 2-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                                  370 3-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                                  371 2-isoxazolyl(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                               372 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                    373 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CH.sub.3 -4-MeO-phenyl                 374 cPr-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                  375 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                       376 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                         377 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-phenyl                                        378 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                        379 (cBu).sub.2 CH 2-CH.sub.3 -4-MeO-phenyl                                    380 phenyl(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                                     381 2-furanyl(cBu)CH 2-CH.sub.3 -4-MeO-phenyl       382 3-furan(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                                    383 2-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                                  384 3-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                                  385 2-isoxazolyl(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                               386 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                    387 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CH.sub.3 -4-MeO-phenyl                 388 cBu-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                  389 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                       390 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                         391 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-phenyl                                        392 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-phenyl                                        393 (cPr).sub.2 CH 2,4-diCH.sub.3 -phenyl                                      394 phenyl(cPr)CH 2,4-diCH.sub.3 -phenyl                                       395 2-furanyl(cPr)CH 2,4-diCH.sub.3 -phenyl                                    396 3-furan(cPr)CH 2,4-diCH.sub.3 -phenyl                                      397 2-thienyl(cPr)CH 2,4-diCH.sub.3 -phenyl                                    398 3-thienyl(cPr)CH 2,4-diCH.sub.3 -phenyl                                    399 2-isoxazolyl(cPr)CH 2,4-diCH.sub.3                                        -phenyl                                              400 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCH.sub.3 -phenyl                      401 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCH.sub.3 -phenyl                   402 cPr-CH(CH.sub.3) 2,4-diCH.sub.3 -phenyl                                    403 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCH.sub.3 -phenyl                         404 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCH.sub.3 -phenyl                                           405 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCH.sub                                 .3 -phenyl                                           406 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCH.sub.3 -phenyl                                          407 (cBu).sub.2 CH 2,4-diCH.sub.3 -phenyl                                      408 phenyl(cBu)CH 2,4-diCH.sub.3 -phenyl                                       409 2-furanyl(cBu)CH 2,4-diCH.sub.3 -phenyl                                    410 3-furan(cBu)CH 2,4-diCH.sub.3 -phenyl                                      411 2-thienyl(cBu)CH 2,4-diCH.sub.3 -phenyl                                    412 3-thienyl(cBu)CH 2,4-diCH.sub.3 -phenyl                                    413 2-isoxazolyl(cBu)CH 2,4-diCH.sub.3                                        -phenyl                                              414 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCH.sub.3 -phenyl                      415 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCH.sub.3 -phenyl                   416 cBu-CH(CH.sub.3) 2,4-diCH.sub.3 -phenyl                                    417 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCH.sub.3 -phenyl                         418 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCH.sub.3 -phenyl                                           419 1-cBu-CH(CH.sub.2 OCH.sub.3 2,4-diCH.sub.                                 3 -phenyl                                            420 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCH.sub.3 -phenyl                                          421 (cPr).sub.2 CH 2-CH.sub.3 -4-(CH.sub.3).s                                 ub.2 N-phenyl                                        422 phenyl(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                      423 2-furanyl(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   424 3-furan(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                     425 2-thienyl(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   426 3-thienyl(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   427 2-isoxazolyl(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                                           428 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3                                  -4-(CH.sub.3).sub.2 N-phenyl                        429 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2                                     N-phenyl                                             430 cPr-CH(CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   431 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl        432 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                  N-phenyl                                             433 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                          N-phenyl                                             434 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                  N-phenyl                                            435 (cBu).sub.2 CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                     436 phenyl(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                      437 2-furanyl(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   438 3-furan(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                     439 2-thienyl(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   440 3-thienyl(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   441 2-isoxazolyl(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                                           442 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3                                  -4-(CH.sub.3).sub.2 N-phenyl                        443 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-CH.sub.3 -4-(CH.sub.3).sub.2                                     N-phenyl                                             444 cBu-CH(CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl                   445 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2 N-phenyl        446 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                  N-phenyl                                             447 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                          N-phenyl                                             448 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-(CH.sub.3).sub.2                                  N-phenyl                                            449 (cPr).sub.2 CH 2-MeO-4-CH.sub.3 -phenyl                                    450 phenyl(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                                     451 2-furanyl(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                                  452 3-furan(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                                    453 2-thienyl(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                                  454 3-thienyl(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                                  455 2-isoxazolyl(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                               456 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                    457 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-MeO-4-CH.sub.3 -phenyl                 458 cPr-CH(CH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                  459 1-cPr-CH(CH.sub.2 CH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                       460 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                         461 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-CH.s                                 ub.3 -phenyl                                         462 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                        463 (cBu).sub.2 CH 2-MeO-4-CH.sub.3 -phenyl                                    464 phenyl(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                                     465 2-furanyl(cBu)CH 2-MeO-4-CH.sub.3                                         -phenyl                                              466 3-furan(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                                    467 2-thienyl(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                                  468 3-thienyl(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                                  469 2-isoxazolyl(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                               470 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                    471 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-MeO-4-CH.sub.3 -phenyl                 472 cBu-CH(CH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                  473 1-cBu-CH(CH.sub.2 CH3) 2-MeO-4-CH.sub.3 -phenyl                            474 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                         475 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-CH.s                                 ub.3 -phenyl                                         476 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-CH.sub.3 -phenyl                                        477 (cPr).sub.2 CH 2-MeO-4-CF.sub.3 -phenyl                                    478 phenyl(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                                     479 2-furanyl(cPr)CH 2-MeO-4-CF.sub.3                                         -phenyl                                              480 3-furan(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                                    481 2-thienyl(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                                  482 3-thienyl(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                                  483 2-isoxazolyl(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                               484 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                    485 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-MeO-4-CF.sub.3 -phenyl                 486 cPr-CH(CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                  487 1-cPr-CH(CH.sub.2 CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                       488 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                         489 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-CF.s                                 ub.3 -phenyl                                         490 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                        491 (cBu).sub.2 CH 2-MeO-4-CF.sub.3 -phenyl                                    492 phenyl(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                                     493 2-furanyl(cBu)CH 2-MeO-4-CF.sub.3                                         -phenyl                                              494 3-furan(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                                    495 2-thienyl(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                                  496 3-thienyl(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                                  497 2-isoxazolyl(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                               498 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                    499 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-MeO-4-CF.sub.3 -phenyl                 500 cBu-CH(CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                  501 1-cBu-CH(CH.sub.2 CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                       502 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                         503 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-CF.s                                 ub.3 -phenyl                                         504 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-CF.sub.3 -phenyl                                        505 (cPr).sub.2 CH 2-MeO-4-Cl-phenyl                                           506 phenyl(cPr)CH 2-MeO-4-Cl-phenyl                 507 2-furanyl(cPr)CH 2-MeO-4-Cl-phenyl                                         508 3-furan(cPr)CH 2-MeO-4-Cl-phenyl                                           509 2-thienyl(cPr)CH 2-MeO-4-Cl-phenyl                                         510 3-thienyl(cPr)CH 2-MeO-4-Cl-phenyl                                         511 2-isoxazolyl(cPr)CH 2-MeO-4-Cl-phenyl                                      512 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-MeO-4-Cl-phenyl                           513 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-MeO-4-Cl-phenyl                        514 cPr-CH(CH.sub.3) 2-MeO-4-Cl-phenyl                                         515 1-cPr-CH(CH.sub.2 CH.sub.3) 2-MeO-4-Cl-phenyl                              516 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-Cl-phenyl                     517 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-Cl-phenyl                             518 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-Cl-phenyl                    519 (cBu).sub.2 CH 2-MeO-4-Cl-phenyl                                           520 phenyl(cBu)CH 2-MeO-4-Cl-phenyl                                            521 2-furanyl(cBu)CH 2-MeO-4-Cl-phenyl                                         522 3-furan(cBu)CH 2-MeO-4-Cl-phenyl                                           523 2-thienyl(cBu)CH 2-MeO-4-Cl-phenyl                                         524 3-thienyl(cBu)CH 2-MeO-4-Cl-phenyl                                         525 2-isoxazolyl(cBu)CH 2-MeO-4-Cl-phenyl                                      526 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-MeO-4-Cl-phenyl                           527 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-MeO-4-Cl-phenyl                        528 cBu-CH(CH.sub.3) 2-MeO-4-Cl-phenyl                                         529 1-cBu-CH(CH.sub.2 CH.sub.3) 2-MeO-4-Cl-phenyl                              530 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-MeO-4-Cl-phenyl                     531 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-MeO-4-Cl-phenyl                             532 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-MeO-4-Cl-phenyl                    533 (cPr).sub.2 CH 2,4-diMeO-phenyl                                            534 phenyl(cPr)CH 2,4-diMeO-phenyl                                             535 2-furanyl(cPr)CH 2,4-diMeO-phenyl                                          536 3-furan(cPr)CH 2,4-diMeO-phenyl                                            537 2-thienyl(cPr)CH 2,4-diMeO-phenyl                                          538 3-thienyl(cPr)CH 2,4-diMeO-phenyl                                          539 2-isoxazolyl(cPr)CH 2,4-diMeO-phenyl                                       540 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diMeO-phenyl                            541 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diMeO-phenyl                         542 cPr-CH(CH.sub.3) 2,4-diMeO-phenyl                                          543 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diMeO-phenyl                               544 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diMeO-phenyl                      545 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diMeO-phenyl                              546 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diMeO-phenyl                     547 (cBu).sub.2 CH 2,4-diMeO-phenyl                                            548 phenyl(cBu)CH 2,4-diMeO-phenyl                                             549 2-furanyl(cBu)CH 2,4-diMeO-phenyl                                          550 3-furan(cBu)CH 2,4-diMeO-phenyl                                            551 2-thienyl(cBu)CH 2,4-diMeO-phenyl                                          552 3-thienyl(cBu)CH 2,4-diMeO-phenyl                                          553 2-isoxazolyl(cBu)CH 2,4-diMeO-phenyl                                       554 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diMeO-phenyl                            555 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diMeO-phenyl                         556 cBu-CH(CH.sub.3) 2,4-diMeO-phenyl                                          557 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diMeO-phenyl                               558 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diMeO-phenyl                      559 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diMeO-phenyl                              560 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diMeO-phenyl                     561 (cPr).sub.2 CH 2,4-diCl-6-CH.sub.3 -phenyl                                 562 phenyl(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                                  563 2-furanyl(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                               564 3-furan(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                                 565 2-thienyl(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                               566 3-thienyl(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                               567 2-isoxazolyl(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                            568 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                 569 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCl-6-CH.sub.3 -phenyl                                         570 cPr-CH(CH.sub.3) 2,4-diCl-6-CH.sub.3                                      -phenyl                                              571 1-CPr-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                    572 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                                      573 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-C                                 H.sub.3 -phenyl                                      574 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                                     575 (cBu).sub.2 CH 2,4-diCl-6-CH.sub.3                                        -phenyl                                              576 phenyl(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                                  577 2-furanyl(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                               578 3-furan(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                                 579 2-thienyl(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                               580 3-thienyl(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                               581 2-isoxazolyl(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                            582 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                 583 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCl-6-CH.sub.3 -phenyl                                         584 cBu-CH(CH.sub.3) 2,4-diCl-6-CH.sub.3                                      -phenyl                                              585 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                    586 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                                      587 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-C                                 H.sub.3 -phenyl                                      588 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-CH.sub.3 -phenyl                                     589 (cPr).sub.2 CH 2,4-diCl-5-F-phenyl                                         590 phenyl(cPr)CH 2,4-diCl-5-F-phenyl                                          591 2-furanyl(cPr)CH 2,4-diCl-5-F-phenyl                                       592 3-furan(cPr)CH 2,4-diCl-5-F-phenyl                                         593 2-thienyl(cPr)CH 2,4-diCl-5-F-phenyl                                       594 3-thienyl(cPr)CH 2,4-diCl-5-F-phenyl                                       595 2-isoxazolyl(cPr)CH 2,4-diCl-5-F-phenyl                                    596 2-(5-CH.sub.3 -furanyl(cPr)CH 2,4-diCl-5-                                 F-phenyl                                             597 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCl-5-F-phenyl                      598 cPr-CH(CH.sub.3) 2,4-diCl-5-F-phenyl                                       599 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCl-5-F-phenyl                            600 1-CPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-5-F-phenyl                   601 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-5-F-phenyl                           602 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-5-F-phenyl                  603 (cBu).sub.2 CH 2,4-diCl-5-F-phenyl                                         604 phenyl(cBu)CH 2,4-diCl-5-F-phenyl                                          605 2-furanyl(cBu)CH 2,4-diCl-5-F-phenyl                                       606 3-furan(cBu)CH 2,4-diCl-5-F-phenyl                                         607 2-thienyl(cBu)CH 2,4-diCl-5-F-phenyl                                       608 3-thienyl(cBu)CH 2,4-diCl-5-F-phenyl                                       609 2-isoxazolyl(cBu)CH 2,4-diCl-5-F-phenyl                                    610 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCl-5-F-phenyl                         611 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCl-5-F-phenyl                      612 cBu-CH(CH.sub.3) 2,4-diCl-5-F-phenyl                                       613 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCl-5-F-phenyl                            614 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-5-F-phenyl                   615 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-5-F-phenyl                           616 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-5-F-phenyl                  617 (cPr).sub.2 CH 2,4-diCl-6-MeS-phenyl                                       618 phenyl(cPr)CH 2,4-diCl-6-MeS-phenyl                                        619 2-furanyl(cPr)CH 2,4-diCl-6-MeS-phenyl                                     620 3-furan(cPr)CH 2,4-diCl-6-MeS-phenyl                                       621 2-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl                                     622 3-thienyl(cPr)CH 2,4-diCl-6-MeS-phenyl                                     623 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeS-phenyl                                  624 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCl-6-MeS-phenyl                       625 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCl-6-MeS-phenyl                    626 cPr-CH(CH.sub.3) 2,4-diCl-6-MeS-phenyl                                     627 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-MeS-phenyl                          628 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-MeS-phenyl                 629 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeS-phenyl                         630 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeS-phenyl                                           631 (cBu).sub.2 CH 2,4-diCl-6-MeS-phenyl                                       632 phenyl(cBu)CH 2,4-diCl-6-MeS-phenyl                                        633 2-furanyl(cBu)CH 2,4-diCl-6-MeS-phenyl                                     634 3-furan(cBu)CH 2,4-diCl-6-MeS-phenyl                                       635 2-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl                                     636 3-thienyl(cBu)CH 2,4-diCl-6-MeS-phenyl                                     637 2-isoxazolyl(cBu)CH 2,4-diCl-6-MeS-phenyl       638 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCl-6-MeS-phenyl                       639 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCl-6-MeS-phenyl                    640 cBu-CH(CH.sub.3) 2,4-diCl-6-MeS-phenyl                                     641 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-MeS-phenyl                          642 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-MeS-phenyl                 643 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeS-phenyl                         644 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeS-phenyl                                           645 (cPr).sub.2 CH 2,4-diCl-6-MeO-phenyl                                       646 phenyl(cPr)CH 2,4-diCl-6-MeO-phenyl                                        647 2-furanyl(cPr)CH 2,4-diCl-6-MeO-phenyl                                     648 3-furan(cPr)CH 2,4-diCl-6-MeO-phenyl                                       649 2-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl                                     650 3-thienyl(cPr)CH 2,4-diCl-6-MeO-phenyl                                     651 2-isoxazolyl(cPr)CH 2,4-diCl-6-MeO-phenyl       652 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4-diCl-6-MeO-phenyl                       653 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4-diCl-6-MeO-phenyl                    654 cPr-CH(CH.sub.3) 2,4-diCl-6-MeO-phenyl                                     655 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-MeO-phenyl                          656 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-MeO-phenyl                 657 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeO-phenyl                         658 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeO-phenyl                                           659 (cBu).sub.2 CH 2,4-diCl-6-MeO-phenyl                                       660 phenyl(cBu)CH 2,4-diCl-6-MeO-phenyl                                        661 2-furanyl(cBu)CH 2,4-diCl-6-MeO-phenyl                                     662 3-furan(cBu)CH 2,4-diCl-6-MeO-phenyl                                       663 2-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl                                     664 3-thienyl(cBu)CH 2,4-diCl-6-MeO-phenyl                                     665 2-isaxazolyl(cBu)CH 2,4-diCl-6-MeO-phenyl       666 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4-diCl-6-MeO-phenyl                       667 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4-diCl-6-MeO-phenyl                    668 cBu-CH(CH.sub.3) 2,4-diCl-6-MeO-phenyl                                     669 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4-diCl-6-MeO-phenyl                          670 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4-diCl-6-MeO-phenyl                 671 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeO-phenyl                         672 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4-diCl-6-MeO-phenyl                                           673 (cPr).sub.2 CH 2,5-diCl-4-MeO-phenyl                                       674 phenyl(cPr)CH 2,5-diCl-4-MeO-phenyl                                        675 2-furanyl(cPr)CH 2,5-diCl-4-MeO-phenyl                                     676 3-furan(cPr)CH 2,5-diCl-4-MeO-phenyl                                       677 2-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl                                     678 3-thienyl(cPr)CH 2,5-diCl-4-MeO-phenyl                                     679 2-isoxazolyl(cPr)CH 2,5-diCl-4-MeO-phenyl       680 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,5-diCl-4-MeO-phenyl                       681 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,5-diCl-4-MeO-phenyl                    682 cPr-CH(CH.sub.3) 2,5-diCl-4-MeO-phenyl                                     683 1-cPr-CH(CH.sub.2 CH.sub.3) 2,5-diCl-4-MeO-phenyl                          684 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCl-4-MeO-phenyl                 685 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,5-diCl-4-MeO-phenyl                         686 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCl-4-MeO-phenyl                                           687 (cBu).sub.2 CH 2,5-diCl-4-MeO-phenyl                                       688 phenyl(cBu)CH 2,5-diCl-4-MeO-phenyl                                        689 2-furanyl(cBu)CH 2,5-diCl-4-MeO-phenyl                                     690 3-furan(cBu)CH 2,5-diCl-4-MeO-phenyl                                       691 2-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl                                     692 3-thienyl(cBu)CH 2,5-diCl-4-MeO-phenyl                                     693 2-isoxazolyl(cBu)CH 2,5-diCl-4-MeO-phenyl       694 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,5-diCl-4-MeO-phenyl                       695 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,5-diCl-4-MeO-phenyl                    696 cBu-CH(CH.sub.3) 2,5-diCl-4-MeO-phenyl                                     697 1-cBu-CH(CH.sub.2 CH.sub.3) 2,5-diCl-4-MeO-phenyl                          698 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCl-4-MeO-phenyl                 699 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,5-diCl-4-MeO-phenyl                         700 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCl-4-MeO-phenyl                                           701 (cPr).sub.2 CH 2,4,6-triCl-phenyl                                          702 phenyl(cPr)CH 2,4,6-triCl-phenyl                                           703 2-furanyl(cPr)CH 2,4,6-triCl-phenyl                                        704 3-furan(cPr)CH 2,4,6-triCl-phenyl                                          705 2-thienyl(cPr)CH 2,4,6-triCl-phenyl                                        706 3-thienyl(cPr)CH 2,4,6-triCl-phenyl                                        707 2-isoxazolyl(cPr)CH 2,4,6-triCl-phenyl                                     708 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4,6-triC                                 l-phenyl                                             709 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4,6-triCl-phenyl                       710 cPr-CH(CH.sub.3) 2,4,6-triCl-phenyl                                        711 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4,6-triCl-phenyl                             712 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4,6-triCl-phenyl                    713 i-cPr-CH(CH.sub.2 OCH.sub.3) 2,4,6-triCl-phenyl                            714 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4,6-triCl-phenyl                   715 (cBu).sub.2 CH 2,4,6-triCl-phenyl                                          716 phenyl(cBu)CH 2,4,6-triCl-phenyl                                           717 2-furanyl(cBu)CH 2,4,6-triCl-phenyl                                        718 3-furan(cBu)CH 2,4,6-triCl-phenyl                                          719 2-thienyl(cBu)CH 2,4,6-triCl-phenyl                                        720 3-thienyl(cBu)CH 2,4,6-triCl-phenyl                                        721 2-isoxazolyl(cBu)CH 2,4,6-triCl-phenyl                                     722 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4,6-triCl-phenyl                          723 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4,6-triCl-phenyl                       724 cBu-CH(CH.sub.3) 2,4,6-triCl-phenyl                                        725 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4,6-triCl-phenyl                             726 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4,6-triCl-phenyl                    727 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4,6-triCl-phenyl                            728 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4,6-triCl-phenyl                   729 (cPr).sub.2 CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                 730 phenyl(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                  731 2-furanyl(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               732 3-furan(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                 733 2-thienyl(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               734 3-thlenyl(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               735 2-isoxazolyl(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                            736 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                 737 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                         738 cPr-CH(CH.sub.3) 2-Cl-4-CH.sub.3                                          -5-F-phenyl                                          739 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                    740 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                                      741 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CH.su                                 b.3 -5-F-phenyl                                      742 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                                     743 (cBu).sub.2 CH 2-Cl-4-CH.sub.3 -5-F-pheny                                 l                                                    744 phenyl(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                  745 2-furanyl(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               746 3-furan(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                 747 2-thienyl(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               748 3-thienyl(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                               749 2-isoxazolyl(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                            750 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                 751 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-CH.sub.3 -5-F-phenyl                                         752 cBu-CH(CH.sub.3) 2-Cl-4-CH.sub.3                                          -5-F-phenyl                                          753 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                    754 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                                      755 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-CH.su                                 b.3 -5-F-phenyl                                      756 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-CH.sub.3 -5-F-phenyl                                     757 (cPr).sub.2 CH 2-Cl-4-MeO-5-CH.sub.3                                      -phenyl                                              758 phenyl(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                759 2-furanyl(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             760 3-furan(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                               761 2-thienyl(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             762 3-thienyl(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             763 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                          764 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                          765 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                         2-Cl-4-MeO-5-CH.sub.3 -phenyl                        766 cPr-CH(CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             767 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                  768 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                    769 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5                                 -CH.sub.3 -phenyl                                    770 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl        771 (cBu).sub.2 CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                               772 phenyl(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                773 2-furanyl(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             774 3-furan(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                               775 2-thienyl(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             776 3-thienyl(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             777 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                          778 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                          779 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                         2-Cl-4-MeO-5-CH.sub.3 -phenyl                        780 cBu-CH(CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                             781 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                  782 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl                                    783 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5                                 -CH.sub.3 -phenyl                                    784 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-CH.sub.3 -phenyl        785 (cPr).sub.2 CH 2-Cl-4-MeO-5-F-phenyl                                       786 phenyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                        787 2-furanyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                     788 3-furan(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                       789 2-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                     790 3-thienyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                     791 2-isoxazolyl(cPr)CH 2-Cl-4-MeO-5-F-phenyl                                  792 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl                       793 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2-Cl-4-MeO-5-F-phenyl                    794 cPr-CH(CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                                     795 1-cPr-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                          796 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                 797 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl                         798 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl                                           799 (cBu).sub.2 CH 2-Cl-4-MeO-5-F-phenyl                                       800 phenyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                                        801 2-furanyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                                     802 3-furan(cBu)CH 2-Cl-4-MeO-5-F-phenyl                                       803 2-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                                     804 3-thienyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl                                     805 2-isoxazolyl(cBu)CH 2-Cl-4-MeO-5-F-phenyl       806 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl                       807 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2-Cl-4-MeO-5-F-phenyl                    808 cBu-CH(CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                                     809 1-cBu-CH(CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                          810 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-Cl-4-MeO-5-F-phenyl                 811 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl                         812 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-Cl-4-MeO-5-F-phenyl                                           813 (cPr).sub.2 CH 2-CH.sub.3 -4-MeO-5-Cl-phe                                 nyl                                                  814 phenyl(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                815 2-furanyl(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             816 3-furan(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                               817 2-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             818 3-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             819 2-isoxazolyl(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                          820 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                          821 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                         2-CH.sub.3 -4-MeO-5-Cl-phenyl                        822 cPr-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             823 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                  824 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                    825 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-5-Cl-phenyl                                   826 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl        827 (cBu).sub.2 CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                               828 phenyl(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                829 2-furanyl(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             830 3-furan(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                               831 2-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             832 3-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             833 2-isoxazolyl(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                          834 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                          835 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                         2-CH.sub.3 -4-MeO-5-Cl-phenyl                        836 cBu-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                             837 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                  838 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl                                    839 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-5-Cl-phenyl                                   840 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-5-Cl-phenyl        841 (cPr).sub.2 CH 2,5-diCH.sub.3 -4-MeO-phenyl                                842 phenyl(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                 843 2-furanyl(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              844 3-furan(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                845 2-thienyl(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              846 3-thienyl(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              847 2-isoxazolyl(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                           848 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                           849 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                         2,5-diCH.sub.3 -4-MeO-phenyl                         850 cPr-CH(CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                              851 1-cPr-CH(CH.sub.2 CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                   852 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                                     853 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,5-diCH.sub                                 .3 -4-MeO-phenyl                                     854 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                                    855 (cBu).sub.2 CH 2,5-diCH.sub.3 -4-MeO-phen                                 yl                                                   856 phenyl(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                 857 2-furanyl(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              858 3-furan(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                859 2-thienyl(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              860 3-thienyl(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                              861 2-isdxazolyl(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                           862 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,5-diCH.sub.3 -4-MeO-phenyl                                           863 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                         2,5-diCH.sub.3 -4-MeO-phenyl                         864 cBu-CH(CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                              865 1-cBu-CH(CH.sub.2 CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                   866 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                                     867 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,5-diCH.sub                                 .3 -4-MeO-phenyl                                     868 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,5-diCH.sub.3 -4-MeO-phenyl                                    869 (cPr).sub.2 CH 2-CH.sub.3 -4-MeO-5-F-phen                                 yl                                                   870 phenyl(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                 871 2-furanyl(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              872 3-furan(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                873 2-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              874 3-thienyl(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              875 2-isoxazolyl(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                           876 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                           877 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                         2-CH.sub.3 -4-MeO-5-F-phenyl                         878 cPr-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                              879 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                   880 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                                     881 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-5-F-phenyl                                    882 l-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                                    883 (cBu).sub.2 CH 2-CH.sub.3 -4-MeO-5-F-phen                                 yl                                                   884 phenyl(cBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                 885 2-furanyl(cBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              886 3-furan(CBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                887 2-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              888 3-thienyl(cBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                              889 2-isoxazolyl(aBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                           890 2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3 -4-MeO-5-F-phenyl                                           891 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                         2-CH.sub.3 -4-MeO-5-F-phenyl                         892 cBu-CH(CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                              893 1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                   894 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                                     895 1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -4-MeO-5-F-phenyl                                    896 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -4-MeO-5-F-phenyl                                    897 (cPr).sub.2 CH 2,4,6-triCH.sub.3 -phenyl        898 phenyl(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                    899 2-furanyl(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                 900 3-furan(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                   901 2-thienyl(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                 902 3-thienyl(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                 903 2-isoxazolyl(cPr)CH 2,4,6-triCH.sub.3 -phenyl                              904 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,4,6-triCH.sub.3 -phenyl                   905 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,4,6-triCH.sub.3 -phenyl                                           906 cPr-CH(CH.sub.3) 2,4,6-triCH.sub.3                                        -phenyl                                              907 1-cPr-CH(CH.sub.2 CH.sub.3) 2,4,6-triCH.sub.3 -phenyl                      908 l-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4,6-triCH.sub.3 -phenyl                                        909 l-cPr-CH(CH.sub.2 OCH.sub.3) 2,4,6-triCH.                                 sub.3 -phenyl                                        910 l-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4,6-triCH.sub.3 -phenyl                                       911 (cBu).sub.2 CH 2,4,6-triCH.sub.3 -phenyl        912 phenyl(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                    913 2-furanyl(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                 914 3-furan(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                   915 2-thienyl(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                 916 3-thienyl(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                 917 2-isoxazolyl(cBu)CH 2,4,6-triCH.sub.3 -phenyl                              918 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,4,6-triCH.sub.3 -phenyl                   919 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,4,6-triCH.sub.3 -phenyl                                           920 cBu-CH(CH.sub.3) 2,4,6-triCH.sub.3                                        -phenyl                                              921 1-cBu-CH(CH.sub.2 CH.sub.3) 2,4,6-triCH.sub.3 -phenyl                      922 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,4,6-triCH.sub.3 -phenyl                                        923 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,4,6-triCH.                                 sub.3 -phenyl                                        924 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,4,6-triCH.sub.3 -phenyl                                       925 (cPr).sub.2 CH 2,6-diMeO-pyrid-3-yl                                        926 phenyl(cPr)CH 2,6-diMeO-pyrid-3-yl                                         927 2-furanyl(cPr)CH 2,6-diMeO-pyrid-3-yl                                      928 3-furan(cPr)CH 2,6-diMeO-pyrid-3-yl                                        929 2-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl                                      930 3-thienyl(cPr)CH 2,6-diMeO-pyrid-3-yl                                      931 2-isoxazolyl(cPr)CH 2,6-diMeO-pyrid-3-yl        932 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,6-diMeO-pyrid-3-yl                        933 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,6-diMeO-pyrid-3-yl                     934 cPr-CH(CH.sub.3) 2,6-diMeO-pyrid-3-yl                                      935 1-cPr-CH(CH.sub.2 CH.sub.3) 2,6-diMeO-pyrid-3-yl                           936 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,6-diMeO-pyrid-3-yl                  937 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,6-diMeO-pyrid-3-yl                          938 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,6-diMeO-pyrid-3-yl                 939 (cBu).sub.2 CH 2,6-diMeO-pyrid-3-yl                                        940 phenyl(cBu)CH 2,6-diMeO-pyrid-3-yl                                         941 2-furanyl(cBu)CH 2,6-diMeO-pyrid-3-yl                                      942 3-furan(cBu)CH 2,6-diMeO-pyrid-3-yl                                        943 2-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl                                      944 3-thienyl(cBu)CH 2,6-diMeO-pyrid-3-yl                                      945 2-isoxazolyl(cBu)CH 2,6-diMeO-pyrid-3-yl                                   946 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,6-diMeO-pyrid-3-yl                        947 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,6-diMeO-pyrid-3-yl                     948 cBu-CH(CH.sub.3) 2,6-diMeO-pyrid-3-yl                                      949 1-cBu-CH(CH.sub.2 CH.sub.3) 2,6-diMeO-pyrid-3-yl                           950 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,6-diMeO-pyrid-3-yl                  951 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,6-diMeO-pyrid-3-yl                          952 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,6-diMeO-pyrid-3-yl                 953 (cPr).sub.2 CH 2,6-diCH.sub.3 -pyrid-3-yl                                  954 phenyl(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                   955 2-furanyl(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                956 3-furan(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                  957 2-thienyl(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                958 3-thienyl(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                959 2-isoxazolyl(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                             960 2-(5-CH.sub.3 -furanyl)(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                  961 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH 2,6-diCH.sub.3 -pyrid-3-yl                                          962 cPr-CH(CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-                                 yl                                                   963 1-cPr-CH(CH.sub.2 CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                     964 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                                       965 1-cPr-CH(CH.sub.2 OCH.sub.3) 2,6-diCH.sub                                 .3 -pyrid-3-yl                                       966 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                                      967 (cBu).sub.2 CH 2,6-diCH.sub.3 -pyrid-3-yl       968 phenyl(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                   969 2-furanyl(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                970 3-furan(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                  971 2-thienyl(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                972 3-thienyl(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                973 2-isoxazolyl(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                             974 2-(5-CH.sub.3 -furanyl)(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                  975 2-(4-CH.sub.3 -isoxazolyl)(cBu)CH 2,6-diCH.sub.3 -pyrid-3-yl                                          976 cBu-CH(CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-                                 yl                                                   977 1-cBu-CH(CH.sub.2 CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                     978 1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                                       979 1-cBu-CH(CH.sub.2 OCH.sub.3) 2,6-diCH.sub                                 .3 -pyrid-3-yl                                       980 1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2,6-diCH.sub.3 -pyrid-3-yl                                      981 (cPr).sub.2 CH 2-CH.sub.3 -6-MeO-pyrid-3-                                 yl                                                   982 phenyl(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                 983 2-furanyl(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                              984 3-furan(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                985 2-thienyl(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                              986 3-thienyl(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                              987 2-isoxazolyl(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                           988 2-(5-CH.sub.3 -furanyl)(cPr)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                           989 2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                         2-CH.sub.3 -6-MeO-pyrid-3-yl                         990 cPr-CH(CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                              991 1-cPr-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                   992 1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                                     993 1-cPr-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3                                   -6-MeO-pyrid-3-yl                                    994 1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                                    995 (cBu).sub.2 CH 2-CH.sub.3 -6-MeO-pyrid-3-                                 yl                                                   996 phenyl(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                 997 2-furanyl(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                              998 3-furan(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                999 2-thienyl(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                              1000  3-thienyl(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                            1001  2-isoxazolyl(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                         1002  2-(5-CH.sub.3 -furanyl)(cBu)CH 2-CH.sub.3 -6-MeO-pyrid-3-yl                                         1003  2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                       2-CH.sub.3 -6-MeO-pyrid-3-yl                         1004  cBu-CH(CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                            1005  1-cBu-CH(CH.sub.2 CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                 1006  1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl        1007  1-cBu-CH(CH.sub.2 OCH.sub.3) 2-CH.sub.3 -6-MeO-pyrid-3-yl                                           1008  1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3)                                   2-CH.sub.3 -6-MeO-pyrid-3-yl                         1009  (cPr).sub.2 CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                              1010  phenyl(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                               1011  2-furanyl(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1012  3-furan(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                              1013  2-thienyl(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1014  3-thienyl(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1015  2-isoxazolyl(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                         1016  2-(5-CH.sub.3 -furanyl)(cPr)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                                         1017  2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                       4-CH.sub.3 -6-MeO-pyrid-3-yl                         1018  cPr-CH(CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1019  1-cPr-CH(CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                 1020  1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl        1021  1-cPr-CH(CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                                           1022  1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3)                                   4-CH.sub.3 -6-MeO-pyrid-3-yl                         1023  (cBu).sub.2 CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                              1024  phenyl(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                               1025  2-furanyl(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1026  3-furan(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                              1027  2-thienyl(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1028  3-thienyl(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1029  2-isoxazolyl(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                         1030  2-(5-CH.sub.3 -furanyl)(cBu)CH 4-CH.sub.3 -6-MeO-pyrid-3-yl                                         1031  2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                       4-CH.sub.3 -6-MeO-pyrid-3-yl                         1032  cBu-CH(CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                            1033  1-cBu-CH(CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                 1034  1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl        1035  1-cBu-CH(CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-MeO-pyrid-3-yl                                           1036  1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3)                                   4-CH.sub.3 -6-MeO-pyrid-3-yl                         1037  (cPr).sub.2 CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                          1038  phenyl(cPr)CH 4-CH.sub.3 -6-(CH.sub.3).                                 sub.2 N-pyrid-3-yl                                   1039  2-furanyl(cPr)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                        1040  3-furan(cPr)CH 4-CH.sub.3 -6-(CH.sub.3)                                 .sub.2 N-pyrid-3-yl                                  1041  2-thienyl(cPr)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                        1042  3-thienyl(cPr)CH 4-CH.sub.3 -6-(CH.sub.                                 3).sub.2 N-pyrid-3-yl                                1043  2-isoxazolyl(cPr)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1044  2-(5-CH.sub.3 -furanyl)(cPr)CH                                          4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1045  2-(4-CH.sub.3 -isoxazolyl)(cPr)CH                                       4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1046  cPr-CH(CH.sub.3) 4-CH.sub.3 -6-(CH.sub.                                 3).sub.2 N-pyrid-3-yl                                1047  1-cPr-CH(CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.2                                         N-pyrid-3-yl                                         1048  1-cPr-CH(CH.sub.2 CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.                                 2 N-pyrid-3-yl                                       1049  1-cPr-CH(CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.2                                        N-pyrid-3-yl                                         1050  1-cPr-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub                                 .2 N-pyrid-3-yl                                      1051  (cBu).sub.2 CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                          1052  phenyl(cBu)CH 4-CH.sub.3 -6-(CH.sub.3).                                 sub.2 N-pyrid-3-yl                                   1053  2-furanyl(cBu)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                        1054  3-furan(cBu)CH 4-CH.sub.3 -6-(CH.sub.3)                                 .sub.2 N-pyrid-3-yl                                  1055  2-thienyl(cBu)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                        1056  3-thienyl(cBu)CH 4-CH.sub.3 -6-(CH.sub.                                 3).sub.2 N-pyrid-3-yl                                1057  2-isoxazolyl(cBu)CH 4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1058  2-(5-CH.sub.3 -furanyl)(cBu)CH                                          4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1059  2-(4-CH.sub.3 -isoxazolyl)(cBu)CH                                       4-CH.sub.3 -6-(CH.sub.3).sub.2 N-pyrid-3-yl                                     1060  cBu-CH(CH.sub.3) 4-CH.sub.3 -6-(CH.sub.                                 3).sub.2 N-pyrid-3-yl                                1061  1-cBu-CH(CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.2                                         N-pyrid-3-yl                                         1062  1-cBu-CH(CH.sub.2 CH.sub.2 CH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.                                 2 N-pyrid-3-yl                                       1063  1-cBu-CH(CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub.2                                        N-pyrid-3-yl                                         1064  1-cBu-CH(CH.sub.2 CH.sub.2 OCH.sub.3) 4-CH.sub.3 -6-(CH.sub.3).sub                                 .2 N-pyrid-3-yl                                    ______________________________________                                    

UTILITY

Compounds of this invention are expected to have utility in the treatment of inbalances associated with abnormal levels of CRF in patients suffering from depression, affective disorders, and/or anxiety.

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 μM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFRl receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 μg/l aprotinin, 1 μg/ml leupeptin and 1 μg/ml pepstatin). The homogenate is centrifuged at 40,000×g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer.

After another centrifugation at 40,000×g for 12 min, the pellet is resuspended to a protein concentration of 360 μg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 μl capacity. To each well is added 50 μl of test drug dilutions (final concentration of drugs range from 10⁻¹⁰ -10⁻⁵ M), 100 μl of ¹²⁵ I-ovine-CRF (¹²⁵ I-o-CRF) (final concentration 150 pM) and 150 μl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵ I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980)], which provides Ki values for inhibition which are then used to assess biological activity. Alternatively, tissues and cells which naturally express CRF receptors can be employed in binding assays analogous to those described above.

A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10⁻⁹ to 10⁻⁶ m) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/[³² P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³ H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³² p]cAMP from [³² P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal.

Dosage and Formulation

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed is:
 1. A compound of formula (I): ##STR11## or a stereoisomer or pharmaceutically acceptable salt form thereof; wherein:D is an aryl or heteroaryl group attached through an unsaturated carbon atom; X is selected from the group consisting of CH--R⁹, N--R¹⁰, O, S(O)_(n) and a bond; n is 0, 1 or 2; R¹ is selected from the group consisting of C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, --SO₂ --C₁₋₁₀ alkyl, --SO₂ --R^(1a), and --SO₂ --R^(1b) ; R¹ is substituted with 1 or more substituents selected from the group consisting of --CN, --S(O)_(n) R^(14b), --COR^(13a), --CO₂ R^(13a), --NR^(15a) COR^(13a), --N(COR^(13a))₂, --NR^(15a) CONR^(13a) R^(16a), NR^(15a) CO₂ R^(14b), --CONR^(13a) R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl, wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group --O--, --S(O)_(n) --, --NR^(13a) --, --NCO₂ R^(14b) --, --NCOR^(14b) -- and --NSO₂ R^(14b) --, and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R^(13a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ; R¹ is also substituted with 1-3 substituents independently selected at each occurrence from the group consisting of R^(1a), R^(1b), R^(1c), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --OR^(13a), --NR^(13a) R^(16a), C₁₋₄ alkoxy-C₁₋₄ alkyl and C₃₋₈ cycloalkyl which is substituted with 0-1 R⁹ and in which 0-1 carbons of C₄₋₈ cycloalkyl is replaced by --O--; provided that R¹ is other than a cyclohexyl-(CH₂)₂ -- group; R^(1a) is aryl and is selected from the group consisting of phenyl, naphthyl, indanyl and indenyl, each R^(1a) being substituted with 0-1 --OR¹⁷ and 0-5 substituents independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, SH, --S(O)_(n) R¹⁸, --COR¹⁷, --OC(O)R¹⁸, --NR^(15a) COR¹⁷, --N(COR¹⁷)₂, --NR^(15a) CONR^(17a) R^(19a), --NR^(15a) CO₂ R¹⁸, --NR^(17a) R^(19a), and --CONR^(17a) R^(19a) ; R^(1b) is heteroaryl and is selected from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR¹⁷, SH, --S(O)_(m) R¹⁸, --COR¹⁷, --OC(O)R¹⁸, --NR^(15a) COR¹⁷, --N(COR¹⁷)₂, --NR^(15a) CONR^(17a) R^(19a), --NR^(15a) CO₂ R¹⁸, --NR^(17a) R^(19a), and --CONR^(17a) R^(19a) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R^(15a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ; R^(1c) is heterocyclyl and is a saturated or partially saturated heteroaryl, each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR^(13a), SH, --S(O)_(n) R^(14b), --COR^(13a), --OC(O)R^(14b), --NR^(15a) COR^(13a), --N(COR^(13a))₂, --NR^(15a) CONR^(13a) R^(16a), --NR^(15a) CO₂ R^(14b), --NR^(13a) R^(16a), and --CONR^(13a) R^(16a) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R^(13a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) and wherein any sulfur atom is monooxidized or dioxidized; provided that R¹ is other than a --(CH₂)₁₋₄ -aryl, --(CH₂)₁₋₄ -heteroaryl, or --(CH₂)₁₋₄ -heterocycle, wherein the aryl, heteroaryl, or heterocycle group is substituted or unsubstituted; R² is C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₂₋₄ alkenyl, or C₂₋₄ alkynyl and is substituted with 0-3 substituents selected from the group consisting of --CN, hydroxy, halo and C₁₋₄ alkoxy; alternatively R², in the case where X is a bond, --CN, CF₃ or C₂ F₅ ; R³, R⁷ and R⁸ are independently selected at each occurrence from the group consisting of H, Br, Cl, F, I, --CN, C₁₋₄ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkyl sulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino; provided that when R¹ is unsubstituted C₁₋₁₀ alkyl, then R³ is other than substituted or unsubstituted phenyl; R⁹ and R¹⁰ are independently selected at each occurrence from the group consisting of H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R¹³ is selected from the group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)--, heteroaryl and heteroaryl(C₁₋₄ alkyl)--; R^(13a) and R^(16a) are independently selected at each occurrence from the group consisting of H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁴ is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl)--, heteroaryl and heteroaryl(C₁₋₄ alkyl)-- and benzyl, benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(14a) is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group consisting of C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(14b) is selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁵ is independently selected at each occurrence from the group consisting of H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, phenyl and benzyl, each phenyl or benzyl being substituted on the aryl moiety with 0-3 groups chosen from the group consisting of C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R^(15a) is independently selected at each occurrence from the group consisting of H, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, and C₃₋₆ cycloalkyl-C₁₋₆ alkyl; R¹⁷ is selected at each occurrence from the group consisting of H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ -cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, C₁₋₄ haloalkyl, R¹⁴ S(O)_(n) -C₁₋₄ alkyl, and R^(17b) R^(19b) N--C₂₋₄ alkyl; R¹⁸ and R¹⁹ are independently selected at each occurrence from the group consisting of H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkoxy-C₁₋₂ alkyl, and C₁₋₄ haloalkyl; alternatively, in an NR¹⁷ R⁹ moiety, R¹⁷ and R¹⁹ taken together form 1-pyrrolidinyl, 1-morpholinyl, 1piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R¹³, CO₂ R¹⁴, COR¹⁴ and SO₂ R¹⁴ ; alternatively, in an NR^(17b) R^(19b) moiety, R^(17b) and R^(19b) taken together form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl, wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R¹³, CO₂ R¹⁴, COR¹⁴ and SO₂ R¹⁴ ; R^(17a) and R^(19a) are independently selected at each occurrence from the group consisting of H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl and C₁₋₄ haloalkyl; aryl is independently selected at each occurrence from the group consisting of phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, --OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, --NO₂, SH, --S(O)_(n) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CONR¹⁷ R¹⁹, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF₃, C₂ F₅, OCF₃, SO₂ Me and acetyl; heteroaryl is independently selected at each occurrence from the group consisting of pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted 0-4 carbon atoms with a substituent independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, nitro, --OR¹⁷, SH, --S(O)_(m) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CONR¹⁷ R¹⁹, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, and --CONR¹⁷ R¹⁹ and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group consisting of R¹⁵, CO₂ R^(14a), COR^(14a) and SO₂ R^(14a) ; and, provided that when D is imidazole or triazole, R¹ is other than unsubstituted C₁₋₆ linear or branched alkyl or C₃₋₆ cycloalkyl.
 2. A compound according to claim 1, wherein:R¹ is C₃₋₈ cycloalkyl or C₃₋₆ cycloalkyl-C₁₋₆ alkyl.
 3. A compound according to claim 1, wherein:D is a heteroaryl group attached through an unsaturated carbon atom.
 4. A compound according to claim 1, wherein:D is a phenyl group substituted with 3-5 substituents independently selected at each occurrence from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkoxy-C₁₋₄ alkoxy, --OR¹⁷, Br, Cl, F, I, C₁₋₄ haloalkyl, --CN, --NO₂, SH, --S(O)_(n) R¹⁸, --COR¹⁷, --CO₂ R¹⁷, --OC(O)R¹⁸, --NR¹⁵ COR¹⁷, --N(COR¹⁷)₂, --NR¹⁵ CONR¹⁷ R¹⁹, --NR¹⁵ CO₂ R¹⁸, --NR¹⁷ R¹⁹, --CONR¹⁷ R¹⁹ and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group consisting of C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, --CN, dimethylamino, CF₃, C₂ F₅, OCF3, SO₂ Me and acetyl.
 5. A compound according to claim 1, wherein:R¹ is C₁₋₁₀ alkyl; and R¹ is substituted with 1-3 substituents selected from the group consisting of R^(1a), R^(1b), R^(1c), C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, --OR^(13a), --NR^(13a) R^(16a), --CN, --S(O)_(n) R^(14b), --COR^(13a), --CO₂ R^(13a), --NR^(15a) COR^(13a), N(COR^(13a))₂, NR^(15a) CONR^(13a) R^(16a), --NR^(15a) CO₂ R^(14b), --CONR^(13a) R^(16a), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl wherein the N₄ in the 1-piperazinyl is substituted with 0-1 substituents selected from the group consisting of R^(13a), CO₂ R^(14b), COR^(14b) and SO₂ R^(14b) ; C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from the group consisting of --O--, --S(O)_(n) --, --NR^(13a), --NCO₂ R^(14b) --, --NCOR^(14b) -- and --NSO₂ R^(14b) --; and C₃₋₈ cycloalkyl wherein the C₃₋₈ cycloalkyl is substituted with 0-1 R⁹, and 0-1 carbons in the C₃₋₈ cycloalkyl is replaced by --O--.
 6. A compound according to claim 1, wherein the compound is selected from:1-(1,1-Dicyclopropyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-(1,1-Dicyclopropyl)methyl-2-methoxy-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-(1-cyclopropyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-cyclopentyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-cyclopentyl-2-ethyl-4-(2,4 ,5-trichlorophenyl)-6-methyl-1H-benzimidazole, 1-(1-phenyl)propyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-(1,1-diphenyl)methyl-2-ethyl-4-(2,4,5-trichlorophenyl)-1H-benzimidazole, 1-cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)benzimidazole, 1-(2-methyl)cyclopentyl-2-ethyl-4-(2,4,6-trimethylphenyl)-1H-benzimidazole, 1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4,6-trichlorophenyl)-1H-benzimidazole, 1-(1,1-dicyclopropyl)methyl-2-ethyl-4-(2,4-dichlorophenyl)-1H-benzimidazole 1-(1,1-dicyclopropyl) methyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole, 1-(1-cyclopropyl)butyl-2-ethyl-4-(2-methyl-4-methoxyphenyl)-1H-benzimidazole, 1-cyclopentyl-2-ethyl-4-(2,4,6-trimethyl-3-pyridyl)-1H-benzimidazole.
 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim
 1. 8. A method of treating a subject afflicted with affective disorder, anxiety or depression which comprises administering to the subject the pharmaceutical composition of claim
 6. 